Apparatus and methods for ocular injection

ABSTRACT

An apparatus includes a housing coupled to a medicament container, which is coupled to a needle. An injection assembly is disposed within the housing and includes an energy storage member and an actuation rod. A distal end portion of the actuation rod is disposed within the medicament container. The energy storage member can produce a force on a proximal end portion of the actuation rod sufficient to move the distal end portion of the actuation rod within the medicament container. This can convey at least a portion of a substance from the medicament container via the needle when a distal tip of the needle is disposed within a first region of a target location. The force is insufficient to move the distal end portion of the actuation rod within the medicament container when the distal tip of the needle is disposed within a second region of the target location.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/510,238, entitled “Apparatus and Methods for Ocular Injection,” filedJul. 12, 2019, which is a continuation of U.S. patent application Ser.No. 16/381,213, entitled “Apparatus and Methods for Ocular Injection,”filed Apr. 11, 2019 (now U.S. Pat. No. 10,517,756), which is acontinuation of U.S. patent application Ser. No. 15/946,838, entitled“Apparatus and Methods for Ocular Injection,” filed Apr. 6, 2018 (nowU.S. Pat. No. 10,555,833), which is a continuation of U.S. patentapplication Ser. No. 15/714,441, entitled “Apparatus and Methods forOcular Injection,” filed Sep. 25, 2017 (now U.S. Pat. No. 9,937,075),which is a continuation of U.S. patent application Ser. No. 15/472,551,entitled “Apparatus and Methods for Ocular Injection,” filed Mar. 29,2017 (now U.S. Pat. No. 9,770,361), which is a continuation of U.S.patent application Ser. No. 15/399,239, entitled Apparatus and Methodsfor Ocular Injection, filed Jan. 5, 2017 (now U.S. Pat. No. 9,636,253),which is a continuation of U.S. patent application Ser. No. 14/268,687entitled Apparatus and Methods for Ocular Injection, filed May 2, 2014(now U.S. Pat. No. 9,539,139), which claims priority to and benefit ofU.S. Provisional Patent Application No. 61/953,147, entitled “Apparatusand Methods for Ocular Injection,” filed Mar. 14, 2014, U.S. ProvisionalPatent Application No. 61/944,214, entitled “Apparatus and Methods forControlling the Insertion Depth of a Needle,” filed Feb. 25, 2014, U.S.Provisional Patent Application No. 61/827,371, entitled “Apparatus andMethods for Ocular Injection,” filed May 24, 2013, U.S. ProvisionalPatent Application No. 61/819,052, entitled “Apparatus and Methods forDelivering a Drug to Ocular Tissue,” filed May 3, 2013, and U.S.Provisional Patent Application No. 61/819,048, entitled “Apparatus andMethods for Controlling the Insertion Depth of a Needle,” filed May 3,2013, the disclosures of each of which are incorporated herein byreference in their entirety.

BACKGROUND OF THE INVENTION

The embodiments described herein relate generally to the field ofophthalmic therapies and more particularly to the use of a microneedlefor delivery and/or removal of a substance, such as a fluid therapeuticagent into and/or from ocular tissues for treatment of the eye.

Although needles are used in transdermal and intraocular drug delivery,there remains a need for improved microneedle devices and methods,particularly for delivery of substances (e.g., drugs) into the posteriorregion of the eye. Many inflammatory and proliferative diseases in theposterior region (or other regions) of the eye require long-termpharmacological treatment. Examples of such diseases include maculardegeneration, diabetic retinopathy, and uveitis. It is often difficultto deliver effective doses of a drug to the back of the eye usingconventional delivery methods such as topical application or anintravitreal administration (IVT), which has poor efficacy, and systemicadministration, which often causes significant side effects. Forexample, while eye drops are useful in treating conditions affecting theexterior surface of the eye or tissues at the front of the eye, the eyedrops are often not sufficiently conveyed to the back of the eye, as maybe required for the treatment of some of the retinal diseases listedabove.

Although there have been advances in the past decade regarding theutilization of systemically delivered substances, there are obstacles towide spread adoption of such methods. For example, in certainsituations, direct injection into the eye (e.g., into the vitreous)using conventional 27 gauge or 30 gauge needles and syringes can beeffective. Direct injection, however, can be associated with significantsafety risks, and physicians often require professional training toeffectively perform such methods. Moreover, in some instances, targetedinjection of a therapeutic agent is desirable. In such instances,however, the relatively small anatomic structures of the eye oftenresult in significant challenges to placing a needle at a targetlocation using known devices and methods, especially as they pertain toplacing the distal end of the needle at the desired depth within theeye. Furthermore, IVT administration can have side effects such asincreased intraocular pressure or faster onset of cataract formation.

In addition, many known methods of direct injection of a drug into theeye include inserting a needle or a cannula at an acute angle relativeto a surface of the eye, which can make controlling the depth ofinsertion challenging. For example, some such methods includecontrolling the angular orientation of the needle such that the injectedsubstance exits the needle at a particular location. Moreover, someknown methods of injecting substances into ocular tissue include usingcomplicated visualization system or sensors to control the placement ofthe needle or cannula.

Known devices for ocular injection do not provide the mechanism foradjusting needle length so that the needle can be inserted into the eyeto the desired depth. Known systems also do not provide a reliablemechanism for determining when the needle tip is in the desiredlocation, for example, the suprachoroidal space (SCS) of the eye. Suchshortcomings in known systems and methods are exacerbated because thesize and thickness of various layers included in the eye can varysubstantially from one person to another. For example, the thickness ofthe conjunctiva and the sclera can be substantially different and theirtrue value cannot easily be predetermined via standard techniques.Furthermore, the thickness of these layers can also be different indifferent portions of the eye and at different times of the day in thesame eye and location. Therefore, using known systems and methods it canbe challenging to determine and/or adjust the length of the needle forpuncturing the eye, such that a tip of the needle is at the desireddepth, for example, the SCS. Too short a needle might not penetrate thesclera, and too long a needle can traverse beyond the SCS and damage theretina of the eye. Further, known systems do not provide a convenientway to detect the position of the needle tip within the eye.

Because of the sensitivities associated with intraocular injection(e.g., the sensitivity of the tissue, the potential impact onintraocular pressure and the like), many known systems involve manualinjection. More particularly, many known devices and methods include theuser manually applying a force (e.g., via pushing a plunger with theirthumb or fingers) to expel a fluid (e.g., a drug) into the eye. Becauseof the small needle size and/or the characteristics of the injecteddrug, some such devices and methods involve the use of force levelshigher than that which users are comfortable with applying. For example,some studies have shown that users generally do not like to apply morethan 2N force against the eye during ocular injection. Accordingly, incertain situations a user may not properly deliver the medicament usingknown systems and methods because of their reluctance to apply the forceto fully expel the medicament.

Moreover, injection into different target layers of the eye can causevariability in the amount of the force required for insertion of theneedle and/or injection of the medicament. Different layers of the eyecan have different densities. For example, the sclera generally has ahigher density than the conjunctiva or the SCS. Differences in thedensity of the target region or layer can produce different backpressureagainst the needle exit, i.e., the tip of the needle from which thefluid emerges. Thus, injection into a relatively dense ocular materialsuch as sclera requires more motive pressure to expel the medicamentfrom the needle than is required when injecting a medicament into theSCS.

Furthermore, the injection force to expel the medicament also depends onthe density and viscosity of the liquid medicament, length of theneedle, and diameter of the needle. To inject certain medicaments intothe eye via desired needles (e.g., 27 gauge, 30 gauge, or even smaller)can require more force than many practitioners are comfortable applying.

Intraocular injection can also lead to leakage of intraocular fluids(e.g., aqueous and vitreous humour) or the medicament from a deliverypassageway formed by the needle penetrating into the ocular tissue. Byway of example, if the medicament is delivered to the sclera instead ofthe target ocular tissue layer, for example, the SCS, the highbackpressure of the sclera can force the medicament to leak from theinsertion site. Known systems do not provide a convenient way to preventleakage from insertion site, which can lead to discomfort and loss ofmedicament. This can prolong treatment as well as increase costsassociated with the treatment.

Thus, a need exists for improved devices and methods, which can assistin determining if the needle is at the correct depth, can facilitateinjection of the medicament into ocular tissue, and/or can preventleakage of ocular fluids and/or medicament form the insertion site.

SUMMARY OF THE INVENTION

The embodiments described herein relate generally to the field ofophthalmic therapies and more particularly to the use of a microneedlefor delivery and/or removal of a substance, such as a fluid therapeuticagent into and/or from ocular tissues for treatment of the eye.

In some embodiments, an apparatus includes a housing configured to becoupled to a medicament container. The medicament container isconfigured to be coupled to a needle. An injection assembly is disposedwithin the housing and includes an energy storage member and anactuation rod. A distal end portion of the actuation rod is configuredto be disposed within the medicament container. The energy storagemember is configured to produce a force on a proximal end portion of theactuation rod. The force is sufficient to move the distal end portion ofthe actuation rod within the medicament container to convey at least aportion of a substance from the medicament container via the needle whena distal tip of the needle is disposed within a first region of a targetlocation. Furthermore, the force is insufficient to move the distal endportion of the actuation rod within the medicament container when thedistal tip of the needle is disposed within a second region of thetarget location. In some embodiments, the first region of the targetlocation has a first density and the second region of the targetlocation has a second density, higher than the first density. In someembodiments, the first region of the target location produces a firstbackpressure and the second region of the target location produces asecond backpressure, higher than the first backpressure.

In some embodiments, an apparatus includes a housing configured toreceive a portion of a medicament container, and an adjustment member. Aproximal end portion of the adjustment member is configured to becoupled to the medicament container. A distal end portion of theadjustment member is coupled to a needle. The adjustment member ismovably disposed within the housing such that when the adjustment memberis rotated relative to the housing, the needle is moved through aplurality of discrete increments along a longitudinal axis of thehousing. In some embodiments, the adjustment member defines a lumenconfigured to place the medicament container in fluid communication withthe needle.

In some embodiments, an apparatus includes a hub configured to becoupled to a medical injector. The hub defines a passageway configuredto receive a needle therethrough. The hub has a convex distal endsurface that is configured to contact a target surface of a targettissue when a substance is conveyed through the needle into the targettissue. In some embodiments, the distal end surface includes a sealingportion configured to define a substantially fluid-tight seal with thetarget surface when the distal end surface is in contact with the targetsurface. In such embodiments, the sealing portion can be symmetricalabout the centerline of the passageway.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view of an illustration of the human eye.

FIG. 2 is a cross-sectional view of a portion of the human eye of FIG. 1taken along the line 2-2.

FIGS. 3 and 4 are cross-sectional views of a portion of the human eye ofFIG. 1 taken along the line 3-3, illustrating the suprachoroidal spacewithout and with, respectively, the presence of a fluid.

FIG. 5 is a schematic illustration of an apparatus that includes ahousing and an injection assembly in a first configuration, according toan embodiment.

FIG. 6 shows the apparatus of FIG. 5 in a second configuration,according to an embodiment.

FIG. 7 is a perspective view of a system for delivering a medicament toan eye, according to an embodiment.

FIG. 8 is an exploded view of the system shown in FIG. 7 .

FIG. 9 is a perspective view of a system for delivering a medicament toan eye that includes an injector assembly, according to an embodiment.

FIG. 10 shows the system of FIG. 9 with a first portion of a housingremoved to show the injector assembly.

FIG. 11 shows an exploded view of the system of FIG. 10 .

FIG. 12A shows a side view, FIG. 12B shows a front view, and FIG. 12Cshows a top view of an actuating member included in the system of FIG. 9.

FIG. 13A shows a side view, FIG. 13B shows a front view, and FIG. 13Cshows a top view of a pawl included in the system of FIG. 9 .

FIG. 14A shows a side view of an actuator included in the system of FIG.9 . FIG. 14B shows a side cross-section view of the actuator of FIG. 14Ataken along the line 14B-14B.

FIG. 15 shows a side view of a guide rod included in the system of FIG.9 .

FIGS. 16A-E shows side views of the system of FIG. 9 with a firstportion of the housing removed, the system shown in various states ofoperation.

FIG. 17 show a flow diagram of a method for determining the insertiondepth in a target tissue of a needle included in a medicament deliverydevice using an injection assembly, according to an embodiment.

FIG. 18 show a flow diagram of a method for assisting a user indetermining the insertion depth in a target tissue of a needle includedin a medicament delivery device, and assisting the user in medicamentdelivery using an injection assembly, according to an embodiment.

FIG. 19 shows a schematic illustration of a medical injector thatincludes an adjustment member in a first configuration, according to anembodiment.

FIG. 20 shows the medical injector of FIG. 19 in a second configuration.

FIG. 21 shows a perspective view of a system for delivering a medicamentto an eye that includes a needle assembly, according to an embodiment.

FIG. 22 shows an exploded view of the needle assembly included in thesystem of FIG. 21 .

FIG. 23A, shows a top view, FIG. 23B shows a side view, and FIG. 23Cshows a side cross-section view (taken along the line 23C-23C) of ahousing of the needle assembly of FIG. 22 .

FIG. 24A shows a side view and FIG. 24B shows a top view of a plugincluded in the needle assembly of FIG. 22 .

FIG. 25 shows a perspective view of an adjustment member, a lead screwand a puncturing member included in the needle assembly of FIG. 22 .

FIG. 26A shows a side view of the adjustment member included in theneedle assembly of FIG. 22 . FIG. 26B shows a side cross-section of theadjustment member of FIG. 26A taken along the line 26B-26B.

FIG. 27A shows a side view of the lead screw included in the needleassembly of FIG. 22 . FIG. 27B shows a cross-section view of the leadscrew of FIG. 27A taken along the line 27B-27B.

FIG. 28A shows a side view and FIG. 28B shows a front view of a bushingincluded in the needle assembly of FIG. 22 . FIG. 28C shows across-section view of the bushing of FIG. 28A taken along the line28C-28C.

FIG. 29 shows a side view of a locking pin included in the needleassembly of FIG. 22 .

FIG. 30A shows a side view and FIG. 30B shows a front view of a tabcoupled to the locking pin included in the needle assembly of FIG. 22 .FIG. 30C shows a cross-section view of the tab of FIG. 30A taken alongthe line 30C-30C.

FIG. 31A shows a side view and FIG. 31B shows a front view of a hubincluded in the needle assembly of FIG. 22 , according to an embodiment.FIG. 31C shows a cross-section view of the hub of FIG. 31A taken alongthe line 31C-31C.

FIG. 32 shows a perspective view of the needle assembly of FIG. 22 .

FIG. 33 shows a side cross-section view of the needle assembly of FIG.32 taken along the line 33-33.

FIG. 34 is a cross-sectional view of a portion of a delivery deviceaccording to an embodiment.

FIG. 35 is an enlarged portion of the eye identified in FIG. 1 as regionZ and the portion of the delivery device of FIG. 34 in use, in a firstconfiguration.

FIG. 36 is the enlarged portion of the eye identified in FIG. 1 asregion Z and the portion of the delivery device of FIG. 34 in use, in asecond configuration.

FIG. 37 is a cross-sectional view of a portion of a delivery deviceaccording to an embodiment.

FIG. 38 is a cross-sectional view of a portion of a delivery deviceaccording to an embodiment.

FIG. 39 shows a schematic illustration of a system for delivering amedicament to an eye that includes a hub including a sealing portion,according to an embodiment.

FIG. 40A shows a distal end surface of a hub included in the system ofFIG. 39 in contact with a conjunctiva of an eye and a puncturing memberincluded in the system of FIG. 39 inserted into the sclera of the eye.FIG. 40B shows the distal end of the hub compressing the conjunctiva,FIG. 40C shows the hub further compressing the conjunctiva, and thedistal end of the puncturing member is disposed in proximity of asuprachoroidal space of the eye and is delivering a medicament to thesuprachoroidal space, such that the sealing portion forms asubstantially fluid tight seal with the conjunctiva. FIG. 40D shows anangle θ formed between a centerline of a delivery passageway formed bythe insertion of the puncturing member into the sclera of the eye and asurface line tangent to the conjunctiva.

FIG. 41A shows a finite element analysis (FEA) model of the hub of FIG.40A-D, pressed against the conjunctiva of an eye with a 1N force. FIG.41B shows an enlarged view of a portion shown by the arrow 41B shown inFIG. 41A.

FIG. 42A shows a side view and FIG. 42B shows a front view of a hub thatincludes a convex distal end, according to an embodiment. FIG. 42C showsa cross-section view of the hub of FIG. 42A taken along the line42C-42C.

FIG. 43A shows a side view and FIG. 43B shows a front view of a hub thatincludes a convex distal end, according to an embodiment. FIG. 43C showsa cross-section view of the hub of FIG. 43A taken along the line43C-43C.

FIG. 44A-B show schematic illustrations of a hub included in amedicament delivery system in a first configuration and a secondconfiguration respectively, according to an embodiment.

FIGS. 45A and 45B are schematic illustrations of a portion of a deliverydevice according to an embodiment.

FIGS. 46 and 47 are perspective views of a portion of a delivery deviceaccording to an embodiment.

FIG. 48 is a perspective view of a portion of a delivery deviceaccording to an embodiment.

FIG. 49 is a perspective view of a portion of a delivery deviceaccording to an embodiment.

FIG. 50 is a perspective view of a portion of a delivery deviceaccording to an embodiment.

FIG. 51 is a perspective view of a portion of a delivery deviceaccording to an embodiment.

FIG. 52 is a perspective view of a portion of a delivery deviceaccording to an embodiment.

FIG. 53 is a perspective view of a portion of a delivery deviceaccording to an embodiment.

FIG. 54 is a perspective view of a portion of a delivery device beingused to facilitate an ocular injection, according to an embodiment.

FIG. 55 is a cross-sectional view of the portion of the delivery deviceshown in FIG. 54 .

FIG. 56 shows a perspective view of a delivery device, according to anembodiment.

FIG. 57 shows an exploded view of the delivery device shown in FIG. 56 .

FIG. 58 shows a perspective view of an actuator rod included in thedelivery device of FIG. 56 .

FIG. 59 shows a top perspective view of a plug included in the deliverydevice of FIG. 56 .

FIG. 60 shows a bottom perspective view of the plug of FIG. 59 .

FIG. 61 shows a top perspective view of an actuator included in thedelivery device of FIG. 56 .

FIG. 62 shows a side cross-section view of the actuator of FIG. 61 ,taken along the line 62-62 shown in FIG. 61 .

FIG. 63 shows a top perspective view of a medicament containment chamberincluded in the delivery device of FIG. 56 .

FIG. 64 shows a bottom perspective view of the medicament containmentchamber of FIG. 63 .

FIG. 65 shows a side cross-section view of the medicament containmentchamber of FIG. 63 taken along the line 65-65 shown in FIG. 63 .

FIG. 66 shows a top perspective view of a hub included in the deliverydevice of FIG. 56 .

FIG. 67 show a side cross-section view of the hub of FIG. 66 taken alongthe line 67-67 shown in FIG. 66 .

FIG. 68 shows a top perspective view of a cap included in the deliverydevice of FIG. 56 .

FIG. 69 shows a side cross-section view of the cap of FIG. 68 takenalong the line 69-69 shown in FIG. 68 .

FIGS. 70 and 71 show side cross-section views of the delivery device ofFIG. 56 in a first configuration and a second configuration,respectively.

FIG. 72 shows a perspective view of an injection marker that can beincluded in a delivery system, according to an embodiment.

FIG. 73 shows the injection marker of FIG. 72 being used to mark aninjection site on an eye.

FIG. 74 shows a perspective view of a delivery device and an extractionmember configured to be coupled to the delivery device, according to anembodiment.

FIG. 75 shows a perspective view of the delivery device of FIG. 74 withthe extraction member coupled thereto.

FIG. 76 shows a side cross-section view of the extraction member of FIG.74 .

FIG. 77 shows a perspective view of the delivery device of FIG. 75 and amedicament vial, the extraction member configured to be coupled to thevial.

FIG. 78 shows a side cross-section view of the extraction member andvial of FIG. 77 in an uncoupled configuration.

FIG. 79 shows the extraction member of the delivery device of FIG. 77coupled to the vial.

FIG. 80 shows a side cross-section view of the extraction member andvial of FIG. 79 in a coupled configuration.

FIG. 81 shows a system for delivering a medicament to an eye, accordingto an embodiment, in a first configuration.

FIG. 82 shows an enlarged view of a portion of the system of FIG. 81shown by the arrow 82 in FIG. 81 .

FIG. 83 shows a perspective view of the system of FIG. 81 in a secondconfiguration.

FIGS. 84A-B shows a schematic illustration of a delivery device thatincludes a mechanism to adjust the length of an insertion depth of aneedle included in the delivery device in a first configuration and asecond configuration respectively, according to an embodiment.

FIGS. 85A-B shows a schematic illustration of a delivery device thatincludes an injection assist assembly in a first configuration and asecond configuration respectively, according to an embodiment.

FIG. 86 shows a schematic illustration of a delivery device thatincludes an adjustment member, according to an embodiment.

FIG. 87 shows a schematic illustration of a delivery device thatincludes an injection assembly, according to an embodiment.

FIG. 88 shows a schematic illustration of a portion of a delivery devicethat includes an adjustment member, according to an embodiment.

FIGS. 89A-B show schematic illustrations of a portion of a deliverydevice that includes an adjustment member in a first configuration and asecond configuration respectively, according to an embodiment.

FIGS. 90A-C show a schematic illustrations of a delivery device thatincludes a needle assembly in a first, second and third configuration,according to an embodiment.

FIG. 91 shows a schematic illustration of a delivery device thatincludes a needle assembly and an adjustment member, according to anembodiment.

FIG. 92A shows a perspective view and FIG. 92B shows a sidecross-section view of a delivery device that includes a hub, accordingto an embodiment.

FIG. 93A shows a perspective view of a delivery device that includes ahub, according to an embodiment. FIG. 93B-C show side cross-sectionviews of the delivery device of FIG. 93A in a first configuration and asecond configuration.

FIG. 94A-B show schematic illustrations of a needle configured tocommunicate light inserted a first distance within ocular tissues and asecond distance within the ocular tissue respectively, according to anembodiment.

FIG. 95 shows a speculum configured to position a delivery device forocular injection into an eye, according to an embodiment.

FIG. 96 shows a speculum that includes markings for sizing an eye,according to an embodiment.

FIG. 97 shows a speculum that includes a mount configured to receive amounting portion included in a delivery device and position the deliverydevice for ocular injection into an eye, according to an embodiment.

FIG. 98A shows a perspective view of a one-piece speculum, and FIG. 98Bshows the speculum of FIG. 98A disposed on a eye and delivery devicecoupled thereto, according to an embodiment.

FIG. 99 shows a flow diagram of a method of injecting a substance intoan eye using a medical injector that includes a hub such that a convexdistal end of the hub forms a seal with a target surface to fluidicallyisolate a delivery passageway, according to an embodiment.

DETAILED DESCRIPTION OF THE INVENTION

The embodiments described herein relate to systems and devices fordelivering a fluid (e.g., a drug) or extracting a fluid into the scleraof an eye. Furthermore, embodiments described herein are related tosystems, devices, and methods to assist in the insertion of a deliverymember, for example, a needle or microneedle into the eye, and/or assistin injecting a medicament into a target ocular tissue. Embodimentsdescribed herein are also related to systems, devices, and methods forcontrolling the insertion depth of a delivery member, such as, forexample, a microneedle, into the eye to deliver a therapeutic agent to,for example, a posterior region of the eye (e.g., via the suprachoroidalspace). Embodiments, described herein are also related to systems,devices and methods to form a substantially fluid-tight seal around adelivery passageway formed by insertion of a delivery member, forexample, a microneedle, into the eye to prevent leakage of the substanceand/or ocular fluid from the insertion site.

In some embodiments, the microneedles included in the embodimentsdescribed herein include a bevel, which allows for ease of penetrationinto the sclera and/or suprachoroidal space with minimal collateraldamage. Moreover, in some embodiments, the micro needles disclosedherein can define a narrow lumen (e.g., gauge size greater than or equalto 30 gauge, 32 gauge, 34 gauge, 36 gauge, etc.) to allow forsuprachoroidal drug delivery while minimizing the diameter of the needletrack caused by the insertion of the microneedle. In some embodiments,the lumen and bevel aspect ratio of the microneedles described hereinare distinct from standard 27 gauge and 30 gauge needles, which are nowcommonly used for intraocular injection. For example, the microneedlesincluded in the embodiments described herein can be any of thosedescribed in International Patent Application Publication No.WO2014/036009, entitled, “Apparatus and Methods for Drug Delivery UsingMicroneedles,” filed on Aug. 27, 2013, the disclosure of which isincorporated by reference herein in its entirety (referred to henceforthas the “'009 PCT application”).

In some embodiments, an apparatus includes a housing configured to becoupled to a medicament container. The medicament container isconfigured to be coupled to a needle. An injection assembly is disposedwithin the housing and includes an energy storage member and anactuation rod. A distal end portion of the actuation rod is configuredto be disposed within the medicament container. The energy storagemember is configured to produce a force on a proximal end portion of theactuation rod. The force is sufficient to move the distal end portion ofthe actuation rod within the medicament container to convey at least aportion of a substance from the medicament container via the needle whena distal tip of the needle is disposed within a first region of a targetlocation. Furthermore, the force is insufficient to move the distal endportion of the actuation rod within the medicament container when thedistal tip of the needle is disposed within a second region of thetarget location. In some embodiments, the first region of the targetlocation has a first density and the second region of the targetlocation has a second density, higher than the first density. In someembodiments, the first region of the target location produces a firstbackpressure and the second region of the target location produces asecond backpressure, higher than the first backpressure.

In some embodiments, an apparatus includes a housing configured toreceive at least a portion of a medicament container. The medicamentcontainer is configured to be coupled to a needle. An injection assemblyis disposed within the housing. The injection assembly includes anenergy storage member, an actuation rod, and a release member. A distalend portion of the actuation rod is configured to be disposed within themedicament container. The release member is configured to maintain aposition of the actuation rod relative to the housing when the releasemember is in a first position such that the movement of the housingrelative to the medicament container moves the distal end portion of theactuation rod within the medicament container. The release member isconfigure to release the actuation rod when moved from the firstposition to a second position such that a force produced by the energystorage member moves the distal end portion of the actuation rodrelative to the housing within the medicament container. This conveys atleast a portion of a substance from the medicament container via theneedle. In some embodiments, the force is sufficient to move the distalend portion of the actuation rod within the medicament container when adistal tip of the needle is disposed within a first region of a targetlocation. The force however, is insufficient to move the distal endportion of the actuation rod within the medicament container when thedistal tip of the needle is disposed within a second region of thetarget location.

In some embodiments, a method includes inserting a distal tip of aneedle of a medical injector, which includes a medicament container andan injection assembly, a first distance into a target tissue. Themedicament container is in fluid communication with the needle. Theinjection assembly includes an actuation rod and an energy storagemember that is configured to produce a force on a proximal end portionof the actuation rod. The method further includes releasing theactuation rod of the injection assembly to allow a distal end portion ofthe actuation rod to move within the medicament container in response tothe force. Finally, the method includes inserting, after releasing, thedistal tip of the needle of the medical injector a second distance intothe target tissue if the distal end portion of the actuation rod movesless than a threshold injection distance within the medicament containerin response to the force, the second distance greater than the firstdistance. In some embodiments, the distal end portion of the actuationrod moves a first injection distance within the medicament container inresponse to the force. In such embodiments, the method can furtherinclude moving the injection assembly relative to the medicamentcontainer to move the distal end portion of the actuation rod a secondinjection distance, greater than the first injection distance, withinthe medicament container.

In some embodiments, an apparatus includes a housing configured toreceive a portion of medicament container and an adjustment member. Aproximal end portion of the adjustment member is configured to becoupled to the medicament container. A distal end portion of theadjustment member is coupled to a needle. The adjustment member ismovably disposed within the housing such that when the adjustment memberis rotated relative to the housing, the needle is moved through aplurality of discrete increments along a longitudinal axis of thehousing. In some embodiments, the adjustment member defines a lumenconfigured to place the medicament container in fluid communication withthe needle.

In some embodiments, an apparatus includes a housing configured toreceive a portion of a medicament container and an adjustment member. Aproximal end portion of the adjustment member is configured to becoupled to the medicament container. A distal end portion of theadjustment member is coupled to a needle. The adjustment member definesa plurality of detents such that a protrusion of the housing isconfigured to be removably disposed within each detent from theplurality of detents when the adjustment member is moved relative to thehousing to move the needle relative to the housing through a pluralityof discrete increments. In some embodiments, the protrusion can be abearing movably coupled within the housing. In such embodiments, thebearing is configured to be removably disposed within each detent fromthe plurality of detents when the adjustment member is moved relative tothe housing to move the needle through the plurality of discreteincrements. Furthermore, the apparatus can also include a bias memberconfigured to maintain the bearing within a detent from the plurality ofdetents.

In some embodiments, an apparatus includes a hub configured to becoupled to a medical injector. The hub defines a passageway configuredto receive a needle therethrough. The hub has a convex distal endsurface, which is configured to contact a target surface of a targettissue when a substance is conveyed through the needle into the targettissue. In some embodiments, the distal end surface includes a sealingportion configured to define a substantially fluid-tight seal with thetarget surface when the distal end surface is in contact with the targetsurface.

In some embodiments, a method includes inserting a distal end portion ofa needle of a medical injector into a target tissue to define a deliverypassageway within the target tissue. This is followed by placing aconvex distal end surface of a hub of the medical injector into contactwith a target surface of the target tissue to fluidically isolate thedelivery passageway. Next, the method includes conveying, after theplacing, a substance into the target tissue via the needle. In someembodiments, the target tissue is an eye and the target surface is theconjunctiva of the eye. In some embodiments, the delivery passagewayextends through a sclera of the eye and the conveying includes conveyingthe substance into at least one of a suprachoroidal space or lowerportion of the sclera. In such embodiments, the method can furtherinclude adjusting, before the conveying, a length of the needleextending from the distal end surface of the hub.

In some embodiments, a method includes inserting a distal end portion ofa needle of a medical injector into a target tissue to define a deliverypassageway within the target tissue. The inserting is performed suchthat a centerline of the needle is substantially normal to a targetsurface of the target tissue. This is followed by placing a distal endsurface of a hub of the medical injector into contact with a targetsurface of the target tissue to fluidically isolate the deliverypassageway. Next, the method includes conveying, after the placing, asubstance into the target tissue via the needle. In some embodiments,the delivery is performed such that a centerline of the deliverypassageway and a surface line tangent to the target surface defines anangle of entry of between about 75 degrees and about 105 degrees.

As used herein, the singular forms “a,” “an”, and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, the term “a member” is intended to mean a single member or acombination of members, “a material” is intended to mean one or morematerials, or a combination thereof.

As used herein, the words “proximal” and “distal” refer to the directioncloser to and away from, respectively, an operator (e.g., surgeon,physician, nurse, technician, etc.) who would insert the medical deviceinto the patient, with the tip-end (i.e., distal end) of the deviceinserted inside a patient's body first. Thus, for example, the end of amicroneedle described herein first inserted inside the patient's bodywould be the distal end, while the opposite end of the microneedle(e.g., the end of the medical device being manipulated by the operator)would be the proximal end of the microneedle.

As used herein, a “set” can refer to multiple features or a singularfeature with multiple parts. For example, when referring to set ofwalls, the set of walls can be considered as one wall with distinctportions, or the set of walls can be considered as multiple walls.

As used herein, the terms “about” and “approximately” generally meanplus or minus 10% of the value stated. For example, about 0.5 wouldinclude 0.45 and 0.55, about 10 would include 9 to 11, about 1000 wouldinclude 900 to 1100.

As used herein, the terms “delivery member”, “puncture member”, and“puncturing member” are used interchangeably to refer to an articleconfigured to pierce tissue layers and deliver a substance to a targettissue layer, for example, a needle or a microneedle.

As used herein, the terms “medicament container”, and “medicamentcontainment chamber” are used interchangeably to refer to an articleconfigured to contain a volume of a substance, for example, amedicament.

The term “fluid-tight” is understood to encompass both a hermetic seal(i.e., a seal that is gas-impervious) as well as a seal that isliquid-impervious. The term “substantially” when used in connection with“fluid-tight,” “gas-impervious,” and/or “liquid-impervious” is intendedto convey that, while total fluid imperviousness is desirable, someminimal leakage due to manufacturing tolerances, or other practicalconsiderations (such as, for example, the pressure applied to the sealand/or within the fluid), can occur even in a “substantiallyfluid-tight” seal. Thus, a “substantially fluid-tight” seal includes aseal that prevents the passage of a fluid (including gases, liquidsand/or slurries) therethrough when the seal is maintained at a constantposition and at fluid pressures of less than about 5 psig, less thanabout 10 psig, less than about 20 psig, less than about 30 psig, lessthan about 50 psig, less than about 75 psig, less than about 100 psigand all values in between. Similarly, a “substantially liquid-tight”seal includes a seal that prevents the passage of a liquid (e.g., aliquid medicament) therethrough when the seal is maintained at aconstant position and is exposed to liquid pressures of less than about5 psig, less than about 10 psig, less than about 20 psig, less thanabout 30 psig, less than about 50 psig, less than about 75 psig, lessthan about 100 psig and all values in between.

The embodiments and methods described herein can be used to treat,deliver substances to and/or aspirate substances from, various targettissues in the eye. For reference, FIGS. 1-4 are a various views of ahuman eye 10 (with FIGS. 2-4 being cross-sectional views). Whilespecific regions are identified, those skilled in the art will recognizethat the proceeding identified regions do not constitute the entirety ofthe eye 10, rather the identified regions are presented as a simplifiedexample suitable for the discussion of the embodiments herein. The eye10 includes both an anterior segment 12 (the portion of the eye in frontof and including the lens) and a posterior segment 14 (the portion ofthe eye behind the lens). The anterior segment 12 is bounded by thecornea 16 and the lens 18, while the posterior segment 14 is bounded bythe sclera 20 and the lens 18. The anterior segment 12 is furthersubdivided into the anterior chamber 22, between the iris 24 and thecornea 16, and the posterior chamber 26, between the lens 18 and theiris 24. The cornea 16 and the sclera 20 collectively form a limbus 38at the point at which they meet. The exposed portion of the sclera 20 onthe anterior segment 12 of the eye is protected by a clear membranereferred to as the conjunctiva 45 (see e.g., FIGS. 2 and 3 ). Underlyingthe sclera 20 is the choroid 28 and the retina 27, collectively referredto as retinachoroidal tissue. A vitreous humour 30 (also referred to asthe “vitreous”) is disposed between a ciliary body 32 (including aciliary muscle and a ciliary process) and the retina 27. The anteriorportion of the retina 27 forms an ora serrata 34. The loose connectivetissue, or potential space, between the choroid 28 and the sclera 20 isreferred to as the suprachoroid. FIG. 2 illustrates the cornea 16, whichis composed of the epithelium 40, the Bowman's layer 41, the stroma 42,the Descemet's membrane 43, and the endothelium 44. FIG. 3 illustratesthe sclera 20 with surrounding Tenon's Capsule 46 or conjunctiva 45,suprachoroidal space 36, choroid 28, and retina 27, substantiallywithout fluid and/or tissue separation in the suprachoroidal space 36(i.e., the in this configuration, the space is “potential”suprachoroidal space). As shown in FIG. 3 , the sclera 20 has athickness between about 500 μm and 700 μm. FIG. 4 illustrates the sclera20 with the surrounding Tenon's Capsule 46 or the conjunctiva 45,suprachoroidal space 36, choroid 28, and retina 27, with fluid 50 in thesuprachoroidal space 36.

As used herein, the term “suprachoroidal space,” or SCS which issynonymous with suprachoroid, or suprachoroidia, describes the space (orvolume) and/or potential space (or potential volume) in the region ofthe eye 10 disposed between the sclera 20 and choroid 28. This regionprimarily is composed of closely packed layers of long pigmentedprocesses derived from each of the two adjacent tissues; however, aspace can develop in this region because of fluid or other materialbuildup in the suprachoroidal space and the adjacent tissues. Thesuprachoroidal space can be expanded by fluid buildup because of somedisease state in the eye or because of some trauma or surgicalintervention. In some embodiments, the fluid buildup is intentionallycreated by the delivery, injection and/or infusion of a drug formulationinto the suprachoroid to create and/or expand further the suprachoroidalspace 36 (i.e., by disposing a drug formulation therein). This volumemay serve as a pathway for uveoscleral outflow (i.e., a natural processof the eye moving fluid from one region of the eye to the other through)and may become a space in instances of choroidal detachment from thesclera.

The dashed line in FIG. 1 represents the equator of the eye 10. In someembodiments, the insertion site of any of the microneedles and/ormethods described herein is between the equator and the limbus 38 (i.e.,in the anterior portion 12 of the eye 10) For example, in someembodiments, the insertion site is between about two millimeters and 10millimeters (mm) posterior to the limbus 38. In other embodiments, theinsertion site of the microneedle is at about the equator of the eye 10.In still other embodiments, the insertion site is posterior the equatorof the eye 10. In this manner, a drug formulation can be introduced(e.g., via the microneedle) into the suprachoroidal space 36 at the siteof the insertion and can flow through the suprachoroidal space 36 awayfrom the site of insertion during an infusion event (e.g., duringinjection).

In some embodiments, a system for ocular injection can include amedicament container at least a portion of which is disposed in ahousing that includes an injection assembly. The injection assembly canfacilitate delivery of a substance disposed in a medicament container toa target tissue, for example, the SCS. For example, FIGS. 5-6 , show asystem 100, according to an embodiment. The system 100 includes ahousing 110, an injection assembly 111, a medicament container 130, anda needle 140, in a first configuration and a second configuration,respectively. The system 100 can be configured to deliver a medicamentto region and/or a layer of a target location, for example, an eye of apatient, (e.g., to the SCS of the eye), as described herein.

The housing 110 is configured to be coupled to the medicament container130, and the medicament container 130 is configured to be coupled to theneedle 140. For example, in some embodiments, at least a portion of themedicament container 130 can be disposed within an internal volumedefined by the housing 110. In some embodiments, the medicamentcontainer 130 can be slidably disposed within the housing 110. Thehousing 110 can be a monolithic housing or include two or more portionswhich can be joined together to form the housing 110. As shown, thehousing 110 defines an internal volume within which the injectionassembly 111 is disposed. Mounting features, for example, mounts,notches, grooves, indents, guide rods, slots, or any other suitablemounting features can be disposed in the interval volume defined by thehousing 110 configured to secure at least a portion of the componentsincluded in the injection assembly 111.

The injection assembly 111 includes an energy storage member 146 and anactuation rod 120. In some embodiments, the energy storage member 146can be a spring, for example, helical spring, compression, extension,spring washers, Belleville washer, tapered, any other type of spring. Inother embodiments, the energy storage member 146 can include acompressed gas container, or a container containing a propellant. Theenergy storage member 146 is operatively coupled to a proximal endportion 122 of the actuation rod 120, and produces a force on theproximal end portion 122 of the actuation rod 120.

A distal end portion 124 of the actuation rod 120 is disposed within themedicament container 130. The distal end portion 124 can be coupled toand/or in contact with a plug 128 which is in fluidic communication witha substance M (e.g., a medicament such as, for example, VEGF, a VEGFinhibitor, a combination thereof, or any other medicament describedherein) disposed within an internal volume defined by the medicamentcontainer 130. The distal end portion 124 of the actuation rod 120 isconfigured to be displaced within the internal volume defined by themedicament container 130, for example, due to the force produced by theenergy storage member 146, as described herein. In this manner, theactuation rod 120 can displace the plug 128 within the medicamentcontainer 130 to draw in or expel the substance M from the distal tip142 of the needle 140, as described herein. The sidewalls of the plug128 can be configured to contact the sidewalls of the medicamentcontainer 130 such that the plug 128 forms a substantially fluid-tightseal with the side wall of the medicament container 130, for example, toprevent leakage of the substance M. The plug 128 can be made of an inertand/or biocompatible material which is rigid but soft. Example materialsinclude rubber, silicone, plastic, polymers, any other suitable materialor combination thereof. In some embodiments, the plug 128 can bemonolithically formed with the actuation rod 120.

The needle 140 can be coupled to the medicament container 130 using anysuitable coupling features, for example, Luer connectors, threads,snap-fit, latch, lock, friction fit, or any other suitable couplingfeatures. The needle 140 can include any suitable needle describedherein, for example, a micro needle (e.g., a 27 gauge, 30 gauge, or evensmaller needle). The distal tip 142 of the needle 140 can define a sharptip such that the needle 140 is configured to pierce a target locationT, for example, a bodily tissue (e.g., ocular tissue). In this manner,the distal tip 142 can be disposed within a first region R1 and/or asecond region R2 of the target location T, as described herein. Theneedle 140 defines a lumen 141, which is in fluidic communication withthe substance M disposed within the internal volume defined by themedicament container 130. In this manner, the needle 140 is configuredto establish fluid communication between the medicament container 130and the target location T, for example, the first region R1 of thetarget location T, as described herein. In some embodiments, the firstregion R1 of the target location T can have a first density and thesecond region R2 can have a second density, which is higher than thefirst density. In some embodiments, the first region R1 of the targetlocation T produces a first backpressure on the distal tip 142 of theneedle 140, and the second region R2 produces a second backpressure onthe distal tip 142 of the needle 140, which is higher than the firstbackpressure. In other words, the first region R1 of the target locationT produces a first pressure that resists and/or opposes flow from thedistal tip 142 of the needle 140, and the second region R2 produces asecond pressure that resists and/or opposes flow from the distal tip 142of the needle 140, which is higher than the first pressure. In someembodiments, the target location T can be an eye such that the firstregion R1 is a suprachoroidal space of the eye, and the second region R2is a sclera of the eye.

The force produced on the proximal end portion 122 of the actuation rod120 by the energy storage member 146 can be sufficient to move thedistal end portion 124 of the actuation rod 120 within the medicamentcontainer 130 to convey at least a portion of the substance M from themedicament container 130 via the needle 140 when the distal tip 142 ofthe needle 140 is disposed within the first region R1 (e.g., an SCS ofthe eye) of the target location T. Furthermore, the force can beinsufficient to move the distal end portion 124 of the actuation rod 120within the medicament container 130 when the distal tip 142 of theneedle 140 is disposed within the second region R2 (e.g., the sclera ofthe eye) of the target location T. Said another way, the injectionassembly 111 can be configured to assist a user in delivering at least aportion of the substance M to the region R1, while be configured or“calibrated” to limit and/or prevent delivery to the region R2. In someembodiments, the injection assembly 111 can be configured to inform theuser when the distal tip 142 of the needle 140 is in the target regionof the target location T, for example, the region R1, such that thesubstance M can be delivered to the target region with high confidence.

Expanding further, FIG. 5 shows the apparatus 100 in the firstconfiguration in which the distal tip 142 of the needle 140 is disposedin the second region R2. When the apparatus is actuated, the energystorage member 146 exerts a force in a direction shown by the arrow F onthe proximal end portion 122 of the actuation rod 120. The force Fexerted, however, is insufficient to move the distal end portion 124 ofthe actuation rod 120 within the medicament container 130. For example,the second region R2 (e.g., the sclera of the eye) can produce a secondbackpressure which overcomes the force F, thereby preventing and/orlimiting delivery of the substance M to the second region R2. In otherwords, the apparatus 100 is specifically configured or “calibrated” suchthat the force F is insufficient to convey the substance M to the secondregion R2.

In the second configuration shown in FIG. 6 , the distal tip 142 of theneedle is now disposed in the first region R1 (e.g., the SCS of theeye). Because of the anatomical differences and/or the differences inmaterial properties between the first region R1 and the second regionR2, the force F is sufficient to move the distal end portion 124 of theactuation rod 120 an injection distance within the medicament container130. For example, the force F can be sufficient to overcome a firstbackpressure produced by the first region R1. In this manner, theinjection assembly 111 can be configured to ensure that the injection isinitiated only when the distal tip 142 of the needle is in the firstregion R1 such that the substance M (e.g., a medicament such as, forexample, VEGF, a VEGF inhibitor, a combination thereof, or any othermedicament described herein) can be delivered only to the region R1. Insome embodiments, the force F exerted by the energy storage member 146can be between about 2 N and about 6 N, for example, about 3 N, about 4N, or about 5 N, inclusive of all ranges therebetween. In someembodiments, the actuation rod 120 and the medicament container 130 canbe collectively configured such that the force produces an injectionpressure within the medicament container 130 of between about 100 kPaand about 500 kPa. For example, in some embodiments, the injectionpressure can be about 100 kPa, 110 kPa, 120 kPa, 130 kPa, 140 kPa, 150kPa, 160 kPa, 170 kPa, 180 kPa, 190 kPa, 200 kPa, 220 kPa, 240 kPa, 260kPa, 280 kPa, 300 kPa, 320 kPa, 340 kPa, 360 kPa, 380 kPa, 400 kPa, 420kPa, 440 kPa, 460 kPa, or about 480 kPa, inclusive of all ranges andvalues therebetween. The injection pressure can be sufficient toovercome the backpressure produced by region R1, but insufficient toovercome the backpressure produced by region R2. For example, the forceF can be varied (e.g., by varying the energy storage member 146)depending on the diameter of the medicament container 130 and/or theactuation rod, the viscosity of the substance M, and/or the material ofthe medicament container 130 and/or the actuation rod 120. In thismanner, regardless of the variations in the actuation rod 120, themedicament container 130, and/or the substance M, the injection assembly111 produces an injection pressure within the medicament container ofbetween about 100 kPa and about 500 kPa.

In some embodiments, the injection assembly 111 can be configured to beengaged or disengaged by a user reversibly on demand. For example, theinjection assembly 111 can include an ON/OFF switch which can be engagedby the user to activate or deactivate the injection assembly and/or theenergy storage member 146. By way of example, in such embodiments, theinjection assembly 111 can be activated by the user (e.g., by turningthe injection assembly ON) to release the energy storage member 146 suchthat the energy storage member 146 exerts the force on the proximal endportion 122 of the actuation rod 120 (e.g., as shown in FIG. 6 ) to movethe distal end portion 124 of the energy storage member 146 within themedicament container 130. The user can then deactivate the injectionassembly 111 (e.g., by turning the injection assembly OFF). Thedisengaging can result in the force exerted on the proximal end portion122 of the actuation rod 120 to be removed (e.g., to stop any furthermovement of the actuation rod 120 within the medicament container 130)or reduced. In some embodiments, the injection assembly 111 can beconfigured such that the direction of the force F can be reversed or theactutation rod 120 and/or the energy storage member 146 can be moved inan opposite direction of the arrow F (FIG. 5 ). In this manner, themedical injector 100 can be returned to the first configuration suchthat, for example, the energy storage member 146 and/or the actuationrod 120 can be secured. This can, for example, allow more flexiblity tothe user to perform dry runs or correct a mistake, for example,inadvertent activation of the injection assembly 111 (e.g., duringtransportation to the target tissue), or injection in an incorrectinsertion site (e.g., an undesired location on an eye). In suchembodiments, the energy storage member 146 can include any suitableengagement member which can be reversibly engaged or disengaged by theuser such as, for example, a valve (e.g., a flap valve, a butterflyvalve, or the likes), a diaphragm, a mechanical actuator (e.g., a rackand pinion actuator, a lead screw and nut actuator, a cam, etc.), ahydraulic actuator (e.g., a hydraulic piston), an electromechanicalactuator (e.g., a piezo electric actuator), a magnetic actuator, or anyother suitable energy storage member 146 which can be reversibly engagedby the user. Such an energy storage member 146 can, for example, allowthe medical injector 100 to be moved between the first configuration andthe second configuration on demand.

In some embodiments, the injection assembly 111 can be configured suchthat injection distance traversed by the actuation rod 120 is sufficientto deliver substantially all of the desired dose of the substance M intothe first region R1. In other embodiments, the injection assembly 111can be configured such that the injection distance traversed by theactuation rod 120 is sufficient to deliver only a portion of the desireddose of the substance M into the first region R1. In such embodiments,the injection assembly 111 can be configured to initiate delivery of thesubstance M into the first region R1, for example, to inform the userthat the distal tip 142 of the needle 140 is disposed within the firstregion R1 (e.g., the user would see or otherwise detect that theactuation rod 120 has moved, thus indicating the desired positioning ofthe needle 140). Said another way, the injection assembly 111 can assistthe user in determining whether the distal tip 142 of the needle 140 iswithin the region R1 or not by initiating delivery of the substance M.In such embodiments, the injection distance can be a first injectiondistance. The user can then move the distal end portion 124 of theactuation rod 120 a second injection distance, for example, by applyinga manual force on the actuation rod 120 (e.g., by moving the housing 110relative to the medicament container 130, as described herein). In someembodiments, any suitable delivery mechanism (e.g., a mechanicalactuator or a pump) can be used to move the distal end portion 122 ofthe actuation rod 120 the second injection distance such thatsubstantially all of the desired dose of the substance M is delivered tothe first region R1.

In some embodiments, the proximal end portion 122 of the actuation rod120 moves relative to the housing 110 to move the distal end portion 124of the actuation rod 120 within the medicament container 130, forexample, when the distal tip 142 of the needle 140 is disposed withinthe first region R1 (e.g., the SCS of the eye) of the target location T.For example, in some embodiments, the proximal end portion 122 of theactuation rod 120 can be configured to move freely within the housing110 such that, distal end portion 124 can move within the medicamentcontainer 130 without the housing 110 and the medicament container 130moving relative to each other. This can, for example, ensure that forceF exerted by the energy storage member 146 does not move the housingrelative to the medicament container 130. In this manner, substantiallyall of the force F can be transferred to the proximal end portion 122 ofthe actuation rod 120. In such embodiments, the housing 110 and/or themedicament container 130 can include features, for example, ribs,notches, grooves, indents, locks, latches, high friction, or any othersuitable mechanism, sufficient to prevent the housing 110 and themedicament container 130 from moving relative to each other due to theforce F.

In some embodiments, the injection assembly 111 can include a releasemember (not shown) configure to selectively limit movement of theactuation rod 120 relative to the housing 110. In such embodiments, thehousing 110 can be configured to move relative to the medicamentcontainer 130 to move the distal end portion 124 of the actuation rod120 within the medicament container 130 independently from the force F.In this manner, the release member can be configured to lock orotherwise secure the actuation rod 120, for example, the proximal endportion 122 of the actuation rod 120, and/or the energy storage member146 in the first configuration. This can, for example, bias the energystorage member 146 to exert the force F on the distal end portion 122 ofthe actuation rod 120. In this manner, the movement of the actuation rod120 can be substantially limited within the housing 110 such that anymovement of the housing 110 relative to the medicament container 130also displaces the distal end portion 124 of the actuation rod 120within the medicament container 130. For example, the user can move thehousing 110 relative to the medicament container 130 to move the distalend portion 124 of the actuation rod 120 within the medicament container130. The relative motion can be used to draw the substance M into themedicament container 130 and/or move the distal end portion 124 thesecond injection distance to expel substantially all of the substance Min the first region R1 or any other target region of the targetlocation, as described herein.

In some embodiments, the release member can be configured to movebetween a first position and a second position such that the releasemember is configured to release the energy storage member 146 when therelease member is moved from the first position to the second position.The release member can include any suitable release member such as, forexample, a pawl, lock, latch, or any other suitable release member. Byway of example, in the first position the release member can secure orotherwise engage the proximal end portion 122 of the actuation rod 120,and/or the energy storage member 146, such that the energy storagemember 146 is biased and/or the actuation rod 120 is locked within thehousing 110, as described herein. Once the distal tip 142 of the needle140 is disposed within the second region R2, the release member can bemoved into the second position to release the energy storage member 146and/or the actuation rod 120. Said another way, the release member canbe configured to maintain a position of the actuation rod 120 relativeto the housing 110 when the release member is in the first position suchthat the movement of the housing 110 relative to the medicamentcontainer 130 moves the distal end portion 124 of actuation rod 120within the medicament container. Furthermore, the release member can beconfigured to release the actuation rod 120 when moved from the firstposition to the second position. This can allow the force F produced bythe energy storage member 146 to move the distal end portion 124 of theactuation rod 120 relative to the housing 110 and within the medicamentcontainer 130 and, thereby convey at least a portion of the substance Mfrom the medicament container 130 via the needle 140. In someembodiments, an actuation mechanism, for example, a button, a pull tab,or any other actuation mechanism can be coupled to the release member.The actuation mechanism can, for example, be configured to be engaged bythe user to move the release member into the second position therebyreleasing the actuation rod 120 and/or the energy storage member 146.

In some embodiments, the injection assembly 111 can also include a guiderod (not shown) fixedly coupled to the housing 110. The actuation rod120 can be configured to slide about the guide rod when the energystorage member 146 is released. For example, in some embodiments, atleast a portion of the guide rod can be disposed within a cavity definedin proximal end portion 122 of the actuation rod 120. In someembodiments, the guide rod can be a hollow rod within which the proximalend portion 122 of the actuation rod 120 is disposed. The guide rod canbe configured to ensure that the actuation rod 120 moves within thehousing 110 and/or medicament container 130 substantially along a centerline A_(L) of the apparatus 100. In this manner, the guide rod canprevent any sideways (or lateral) movement of the actuation rod 120.

In some embodiments, a system for ocular injection can include amedicament containment chamber at least a portion of which is disposedin a housing. Referring now to FIGS. 7-8 , in some embodiments, a system1000 includes at least a housing 1110, a medicament containment chamber1310, and an actuator 1320. The system 1000 can be configured to delivera medicament to a region and/or layer of an eye of a patient, forexample, to the SCS of the eye.

The housing 1110 includes a first portion 1110 a and a second portion1110 b, that can be coupled to define an internal volume for housing atleast a portion of the medicament containment chamber 1310 and theactuator 1320. The first portion 1110 a and the second portion 1110 bcan removably or fixedly coupled together using any suitable means, forexamples, screws, nuts, bolts, rivets, adhesives, a snap-fit mechanism,notches, grooves, indents, lock, latch, or any other suitable couplingmechanism. The housing 1110 includes a gripping portion 1112. Aplurality of ribs 1113 are disposed on the gripping portion 1112 toallow a user to easily grip the housing 1110, for example, between theuser's index and/or middle finger, and thumb. A plurality of ridges 1114are disposed on an outer surface of a distal portion of the housing1110. The ridges 1114 can provide an additional gripping surface for theuser to securely hold the housing 1110. For example, a user can grip thegripping portion 1112 with a first hand and grip the ridges 1114 with asecond hand to limit any movement of the housing 1110 during injectionof a medicament disposed in the medicament containment chamber 1310. Aset of ribs (also referred to as sidewalls and/or protrusions) 1116 aredisposed in the internal volume defined by the housing 1110. The ribs1116 are configured to engage an engagement portion 1312 and/or a flange1313 of the medicament containment chamber 1310, for example, to definea range of travel of the actuator 1320, as described herein. Similarlystated, the ribs 1116 are configured to limit movement of the actuator1320 and/or the flange 1313 relative to the housing 1110 during use.

A set of mounts 1118 are disposed at a proximal end, within the interiorregion, of the housing. The mounts 1118 are configured to mount and/orretain an engagement portion 1322 of the actuator 1320, such that alinear translation of the housing 1110 along a longitudinal axis A_(L)of the system 1000 urges the actuator 1320 to also translate along thelongitudinal axis A_(L) relative to the medicament containment chamber1310. A securing member 1119 can be disposed over a distal end of thehousing. The securing member 1119 can be a ring-like member formed froma relatively elastic material, for example, rubber, silicone, plastics,polymers, any other suitable material or combination thereof. Thesecuring member 1119 can be configured to secure the first portion 1110a and the second portion 1110 b of the housing 1110 to each other at adistal end of the housing 1110.

The medicament containment chamber 1310 defines an internal volumeconfigured to house a medicament (e.g., triamcinolone acetonide, VEGF,VEGF inhibitor, or any other medicament described herein). Themedicament containment chamber 1310 includes an engagement portion 1312and a delivery portion 1314. The delivery portion 1314 can include anysuitable coupling feature, for example, a luer connector, threads, asnap-fit, a latch, a lock, a friction fit coupling, or any othersuitable coupling features. The coupling features can be configured tocouple the delivery portion 1314 with a puncturing member (not shown),for example, a microneedle (e.g., a 27 gauge, a 30 gauge needle, or evensmaller micro needle). The puncturing member can be any suitablepuncturing member (such as those described in the '009 PCT application”)configured to pierce a portion of a patient's body, for example, an eye,and to establish fluidic communication between the medicamentcontainment chamber 1310 and the portion of the user's body (e.g., theeye).

The engagement portion 1312 is disposed proximate to the user andincludes a flange 1313. The engagement portion 1312 is disposed in thehousing 1110 such that the ribs 1116 are distal to the flange 1313, andinteract with the flange 1313 to define a range of motion of theactuator 1320 and/or the medicament containment chamber 1310. In someembodiments, the medicament containment chamber 1310 can include acommercially available syringe such as, for example, a BD™ 1CC syringe,or any other commercially available syringe.

The actuator 1320 includes an engagement portion 1322 and a plungerportion (not shown) movably disposed within the internal volume definedby the medicament containment chamber 1310. At least a portion of theactuator 1320 is slidably disposed in the internal volume defined by themedicament containment chamber 1310. Thus, the actuator 1320 can bedisplaced within the internal volume defined by the medicamentcontainment chamber 1310 for drawing the medicament into or expellingthe medicament from the internal volume defined by the medicamentcontainment chamber 1310. The engagement portion 1322 is fixedly mountedin the mounts 1118 of the housing 1110. Thus, any linear displacement ofthe housing 1110 along the longitudinal axis A_(L) of the system 1000also urges the actuator 1320 to slide within the internal volume of themedicament containment chamber 1310.

In use, a user can grip the housing 1110, for example, at the grippingportion 1112 with one hand, and with the other hand grip a portion ofthe medicament containment chamber 1310 disposed outside the housing1110. The user can then displace the housing 1110 relative to themedicament containment chamber 1310. Displacement of the housing 1110also urges the actuator 1320 to slide within the internal volume definedby the medicament containment chamber 1310. The ribs 1116 can preventthe user from sliding the housing 1110 beyond a predetermined thresholdto prevent the actuator 1320 from being separated from the medicamentcontainment chamber 1310. Furthermore, the range of motion can alsodefine a maximum dose of the medicament that can be drawn into theinternal volume of the medicament containment chamber 1310. In thismanner, the user can draw a medicament into the medicament containmentchamber 1310, or inject the medicament into an ocular tissue, forexample, the SCS of an eye.

In some embodiments, a system for injecting a medicament into oculartissue can include an injector assembly configured to produce a force toassist in the delivery of a medicament. Referring now to FIGS. 9 toFIGS. 16A-C, a system 2000 includes a housing 2110, an injector assembly2100, a medicament containment chamber 2310, and an actuator 2320. Thesystem 2000 can be configured to deliver a medicament to a desired layerand/or region of an eye of patient, for example, to the SCS of the eye.

The housing 2110 includes a first portion 2110 a and a second portion2110 b, that can be coupled to define an internal region for housing thecomponents of the injector assembly 2100 and at least a portion of themedicament containment chamber 2310 and/or the actuator 2320. The firstportion 2110 a and the second portion 2110 b can removably or fixedlycoupled together using any suitable means, for examples, screws, nuts,bolts, rivets, adhesives, a snap-fit mechanism, notches, grooves,indents, lock, latch, or any other suitable coupling mechanism. Thehousing 2110 includes a gripping portion 2112 A plurality of ribs 2113are disposed on the gripping portion 2112 to allow a user to easily gripthe housing 2110, for example, between the user's index and/or middlefinger, and thumb. A plurality of ridges 2114 are also disposed on anouter surface of a distal portion of the housing 2110, for example toallow easy gripping of the housing 2110 by the user. For example, a usercan grip the gripping portion 2112 with a first hand and grip the ridges2114 with a second hand to limit any movement of the housing 2110 duringinjection of a medicament disposed in the medicament containment chamber2310. A set of ribs 2116 are disposed in the internal region defined bythe housing 2110. The ribs 2116 (also referred to as shoulders orprotrusions) are configured to engage a flange 2313 included in anengagement portion 2312 of the medicament containment chamber 2310, forexample, to define a range of travel of the actuator 2320 and/or themedicament containment chamber 2310, as described herein. A proximal endof the housing 2110 includes slots 2117 (see FIG. 11 ) configured toreceive at least a portion of an actuating member 2120 included in theinjector assembly 2100, as described herein. A set of mounts 2118 aredisposed at a proximal end, within the interior region, of the housing.The mounts 2118, are configured to mount an engagement portion 2142 of aguide rod 2140 included in the injector assembly 2100. A securing member2119 can be disposed over a distal end of the housing. The securingmember 2119 can be a ring like member formed from a relatively elasticmaterial, for example, rubber, silicone, plastics, polymers, any othersuitable material or combination thereof. The securing member 2119 canbe configured to secure the first portion 2110 a and the second portion2110 b to each other at a distal end of the housing 2110.

The actuating member 2120 (FIGS. 12A-C) is disposed at the proximal endof the housing 2110 and is configured to actuate the injector assembly2100, as described herein. The actuating member 2120 includes anengagement protrusion 2122 and a guide protrusion 2124. At least aportion of the engagement protrusion 2122 and the guide protrusion 2124are slidably disposed in the slots 2117 (see FIG. 11 ). A user canengage an engagement surface 2121 of the actuating member 2120, and movethe actuating member 2120 between a first configuration, in which theengagement protrusion 2122 and the guide protrusion 2124 are partiallydisposed within the internal volume defined by the housing 2110, and asecond configuration, in which the engagement protrusion 2122 and theguide protrusion 2124 are substantially disposed within the internalvolume defined by the housing 2110. Said another way, the actuatingmember 2120 can be moved relative to the housing 2110 between a firstposition (see FIG. 16D) and a second position (FIG. 16E).

The engagement protrusion 2122 is configured to engage a pawl 2130included in the injector assembly 2100 in the second configuration (orposition), as described herein (see FIG. 16E). The guide protrusion 2124is configured to slide within the slots 2117 along with the engagementprotrusion 2122, to prevent any angular motion of the actuating member2120 about the longitudinal axis A_(L). A biasing member 2123, forexample, a spring (e.g., helical spring, compression, extension, springwashers, Belleville washer, tapered, any other type of spring) iscoupled to the engagement protrusion 2122, for example, disposed aroundthe engagement protrusion 2122. The biasing member 2123 is configured tobias the actuating member 2120 in the first configuration (or position).A washer 2125 is coupled to a proximal end of the guide protrusion 2124and is disposed inside the internal volume defined by the housing 2110.The washer 2125 has a diameter, or otherwise cross-section, which issubstantially larger than the diameter or otherwise cross-section of theslots 2117, such that the washer 2125 prevents the actuating member 2120from being removed from the housing 2100.

The pawl 2130 (FIGS. 13A-C) is disposed at the proximal end of theinternal volume defined by the housing 2110. The pawl 2130 includes anengagement portion 2132, a latch 2134, and a biasing portion 2136. A setof protrusions 2137 are disposed on the pawl 2130. The protrusions 2137are configured to pivotally mount the pawl 2130 in the internal volumedefined by the housing 2110. This allows the pawl 2130 to rotate aboutthe protrusions 2137 between a first configuration (or angular position)and a second configuration (or angular position) as described herein.The engagement portion 2132 defines a flat surface, which is configuredto be engaged by the engagement protrusion 2122 of the actuating member2120 (see e.g., FIG. 16E). More particularly, when the actuating member2120 is moved from its first configuration (or position) to its secondconfiguration (or position), the engagement protrusion 2122 can urge thepawl 2130 from the first configuration into the second configuration.The latch 2134 defines a ledge or shoulder configured to engage anengagement portion 2322 of the actuator (or push rod) 2320 in the firstconfiguration, as described herein. The biasing portion 2136 includes athin, beam-like structure configured to elastically bend in the secondconfiguration. In this manner, the biasing member 2136 can urge the pawl2130 into the first configuration, as described herein. For example, inthe first configuration, the latch 2134 can engage the engagementportion 2322 of the actuator 2320 (see FIGS. 16B-16D) and the biasingportion 2136 can be in an extended position (i.e., maintaining theposition of the pawl 2130). A user can engage the engagement portion2121 of the actuating member 2120 and urge it into its secondconfiguration (or position). In the second configuration of theactuating member 2120, the engagement protrusion 2122 can engage theengagement portion 2132 of the pawl 2130. This can urge the pawl 2130 torotate about the protrusions 2137 and move into the secondconfiguration. When the latch 2134 is in the second configuration, thelatch 2134 can disengage from the engagement portion 2322 of theactuator 2320 such that the biasing portion 2136 is bent against thehousing 2110 and is biased (or compressed). The user can then disengagethe actuating member 2120. The biasing member 2123 coupled to theengagement protrusion 2122 can urge the actuating member 2120 back intothe first configuration. This disengages the engagement protrusion 2122from the engagement surface 2132 of the pawl 2130 such that the biasingportion 2136 can urge the pawl 2130 into the first configuration.

The guide rod 2140 (FIG. 15 ) includes a mounting portion 2142 that isimmovably mounted on the mounts 2118 included in the housing 2110.Similarly stated, the guide rod 2140 is coupled within the housing 2110such that movement (distal movement and proximal movement) is limited.At least a portion of the guide rod 2140 is disposed in a cavity 2326defined within the actuator 2320. The guide 2140 rod is configured toprevent lateral motion of the actuator 2320 when the actuator 2320slides in a linear direction along the longitudinal axis A_(L) of thesystem 2000 within the housing 2110, as described in further detailherein. The guide rod 2140 also couples a biasing member 2146 (or energystorage member which is disposed around the guide rod 2140, see e.g.FIG. 16A) between the mounts 2118 and the actuator (or push rod) 2320.The biasing member 2146 can include, for example, a spring, (e.g., ahelical spring, compression, extension, spring washers, Bellevillewasher, tapered, any other type of spring), any other suitable biasingmember or combination thereof. A proximal end of the biasing member 2146is coupled to and/or engaged with the mounting portion 2142 of the guiderod 2140, and a distal end of the biasing member 2146 is coupled toand/or engaged with the engagement portion 2322 of the actuator 2320.The biasing member 2146 is configured to bias the actuator 2320 when theengagement portion 2322 of the actuator 2320 is disposed relative to themounting portion 2142 of the guide rod 2140 in the “readied” position(see e.g., FIGS. 16B-16D). In this manner, the biasing member 2146 canexert a predetermined biasing force on the actuator 2320 to enable orotherwise assist the actuator 2320 to expel a medicament from themedicament containment chamber 2310, as described in further detailherein.

The medicament containment chamber 2310 defines an internal volume 2316configured to house a medicament (e.g., a VEGF, a VEGF inhibitor,triamcinolone acetonide, any other medicament described herein or acombination thereof). The medicament containment chamber 2310 includesan engagement portion 2312 and a delivery portion 2314. The deliveryportion 2314 can include coupling features, for example, luerconnectors, threads, snap-fit, latch, lock, friction fit, or any othersuitable coupling features. The coupling features can be configured tocouple the delivery portion 2314 with a puncturing member (not shown),for example, a microneedle (e.g., a 27 gage, or 30 gage, or even smallerneedle). The puncturing member can be any suitable puncturing member(such as those described in the '009 PCT application) which isconfigured to pierce a portion of a patient's body, for example, an eye,and to establish fluidic communication between the medicamentcontainment chamber 2310 and the portion of the user's body (e.g., theeye). The engagement portion 2312 includes a flange 2313. The engagementportion 2312 is disposed in the housing 2110 such that the ribs 2116 aredistal to the flange 2313, and interact with the flange 2313 to define arange of motion of the actuator 2320 and/or the medicament containmentchamber 2310. Said another way, the ribs 2116 and the flange 2313 canserve in combination as a locking mechanism to prevent the medicamentcontainment chamber 2310 from moving beyond a threshold distance withinthe housing 2110. In some embodiments, the medicament containmentchamber 2310 can include a commercially available syringe such as, forexample, a BD™ 1CC syringe, or any other commercially available syringe.

The actuator (or actuation rod) 2320 (FIGS. 14A-B) includes anengagement portion 2322 and a plunger portion 2324. As described before,the engagement portion 2322 defines a cavity 2326 configured to receiveat least a portion of the guide rod 2140. A proximal end of theengagement portion 2322 is coupled to and/or engaged with the biasingmember 2146, as described before herein. At least a portion of theactuator 2320, for example, the plunger portion 2324, is slidablydisposed in the internal volume 2316 defined by the medicamentcontainment chamber 2310. Thus, the actuator 2320 can be displacedwithin the internal volume 2316 for drawing and/or expelling themedicament from the internal volume 2316 defined by the medicamentcontainment chamber 2310.

As shown in FIGS. 14A and 14B, a protrusion 2325 is disposed at a distalend of the plunger portion 2324. The protrusion 2325 is configured to beinserted into a plug 2328 with close tolerance (e.g., friction-fit). Theplug 2328 can be slidably disposed in the internal volume 2316 of themedicament containment chamber 2310. A distal end of the plug 2328 canbe in fluid communication with the medicament disposed in the internalvolume 2316 defined by the medicament containment chamber 2310. Thesidewalls of the plug 2328 can be in contact with the sidewalls of theinternal volume 2316 such that the plug forms a fluid tight seal toprevent leakage of the medicament. The plug 2328 can be made of an inertand/or biocompatible which is rigid but soft. Example materials includerubber, silicone, plastic, polymers, any other suitable material orcombination thereof.

The injector assembly 2100 is configured to produce a force to inject orotherwise assist in injecting the medicament from the medicamentcontainment chamber 2310 into the ocular tissue, for example, the SCS.Furthermore, the injector assembly 2100 can be configured to exert apredetermined force and/or a force within a desired range on theactuator 2320 sufficient to expel the medicament only when an outlet ofa puncturing member (e.g., a needle such as a 27 gauge, a 30 gauge orany needle described herein) is within or otherwise near the targetinjection site, for example, the SCS. Similarly stated, the injectorassembly 2100 can be configured to exert a predetermined force on theactuator (or push rod) 2320 and/or the plug 2328 such that the actuator2320 and/or the plug 2328 move when the backpressure against the openingof a delivery member (e.g., a puncture member or needle, not shown) isbelow a desired level. As described below, the amount of backpressureagainst the delivery member can be a function of the tissuecharacteristics of the target tissue (e.g., tissue density, presence ofvoids, tissue type, etc.). Thus, the injector assembly 2100 can producemotive force when the opening of the delivery member is within a desiredtarget location (e.g., the SCS). FIGS. 16A to 16E show the system 2000that includes the injector assembly in various states of operation asdescribed herein.

In a first state shown in FIG. 16A, a portion of the medicamentcontainment chamber 2310 is disposed in the housing 2110 of the injectorassembly 2100. The flange 2313 of the medicament containment chamber2310 can be contiguous and/or in contact with the ribs 2116 of thehousing 2110. The actuator 2320 is pushed into the medicamentcontainment chamber 2310 such that the plunger portion 2324 of theactuator 2320 occupies substantially all of the internal volume 2316 ofthe medicament containment chamber 2310 and there is no medicament inthe internal volume 2316. Additionally, the guide rode 2140 is disposedin a first relative position within the actuator (or push rod) 2320. Inthe first state, the biasing member 2146 is coupled to the engagementportion 2322 of the actuator 2320 and is unbiased (or in an expandedconfiguration). Said another way, the system 2000 is unarmed in thefirst state. Thus, in the first state (or configuration), the system2000 can be shipped, stored or the like.

To move the system 2000 to the second state shown in FIG. 16B, the usermoves the medicament containment chamber 2310 proximally relative to theinjector assembly 2100. This can be achieved by applying a force on thehousing 2110 and/or the medicament containment chamber 2310 such thatthe force pushes the medicament containment chamber 2310 into thehousing 2110 in the direction shown by the arrow A. The housing 2110 isshaped and sized to prevent any rotational motion of the medicamentcontainment chamber 2310 relative to the housing 2110. Motion ofmedicament containment chamber 2130 relative to the injector assembly2100, also urges the actuator 2320 to slide over the guide rod 2140 andmove relative to the injector assembly 2100. Thus, when the injectorassembly 2100 is in the second state, the guide rod 2140 is disposed ina second relative position within the actuator (or push rod) 2320.Furthermore, the biasing member 2146 is biased (or compressed) when theinjector assembly 2100 is in the second state. The force is maintaineduntil the latch 2134 of the pawl 2130 engages and secures the engagementportion 2322 of the actuator 2320. The pawl 2130 includes an angledsurface such that the engagement portion 2322 can slide past the latch2134 in a proximal direction but cannot move past the latch 2134 in adistal direction. Thus, in the second state, the system 2000 is “armed”and is ready to be filled with a medicament.

The user can now couple a transfer needle, puncture member and/ordelivery member (not shown) to the delivery portion 2314 of themedicament containment chamber 2310. The puncturing member can beinserted into a container of the medicament, for example, insertedthrough a septum of a vial containing the medicament. The system 2000can then be moved into a third state (or configuration) to fill themedicament containment chamber 2310 with a substance. To move theinjector assembly 2100 to the third state shown in FIG. 16C, a force canbe applied on the medicament containment chamber 2310 and/or the housing2110 to move the medicament containment chamber 2310 distally relativeto the injector assembly 2100 in the direction shown by the arrow B. Inthis manner, the medicament containment chamber 2310 is drawn out of(moved distally relative to) the housing 2110. The engagement portion2322 of the actuator 2320 remains secured by the latch 2134 of the pawl2130 in the third state. Therefore, the relative motion of themedicament containment chamber 2310 to the housing 2110 urges theplunger portion 2324 of the actuator 2320 to slide within the internalvolume 2316 of the medicament containment chamber 2310 until the plungerportion 2324 is proximate to the engagement portion 2312 of themedicament containment chamber 2310. The displacement of the actuator2320 and the plug 2328 creates a suction force within the internalvolume 2316 of the medicament containment chamber 2310, which draws themedicament into the internal volume 2316.

To place the injector assembly 2100 in a fourth state (shown in FIG.16D), the user can move the medicament containment chamber 2310proximally relative to the injector assembly 2100 such that themedicament containment chamber 2310 moves into the housing 2110 as shownby the arrow C. In the fourth state, the medicament containment chamber2310 is partially drawn into the housing 2110. Since the actuator 2320is still secured by the pawl 2130 in the fourth state, moving thehousing 2310 urges the plunger portion 2324 of the actuator 2320 (andthus the plug 2328) to also slide in the internal volume 2316 proximallyrelative to the medicament containment chamber 2310. In this manner, theplunger portion 2324 of the actuator 2320 expels a portion of themedicament from the internal volume 2316. Said another way, the user canexpel air from the internal volume 2316 and/or adjust a dose of themedicament in the fourth state.

Prior to injecting the medicament (i.e., moving the injector assembly2000 to a fifth state shown in FIG. 16E), a puncturing member (e.g., a27 gauge needle, a 30 gauge needle, or any other puncturing membersdescribed herein), or a needle assembly (e.g., the needle assembly 3200or any other needle assembly described herein) can be coupled to thedelivery portion 2314 of the medicament containment chamber 2310. Whilenot shown, a hub can also be coupled to the delivery portion 2314, whichis configured to contact an ocular tissue. The hub can include a hubthat includes a convex distal end, a flat distal end, features foraligning the system 2000 on a surface (e.g., conjunctiva) of the eye, orany other hub described herein. For example, in some embodiments, thehub can include a convex distal end surface configured to form asubstantially fluid-tight seal with a target surface around theinsertion site (see e.g., hub 7270 included in the medical injector7000).

The user can insert the puncturing member into an eye, until an outletof the puncturing member is in or otherwise near a target deliverylayer, for example, the SCS. The user can manually adjust the insertiondepth of the puncturing member or a needle assembly to increase ordecrease the insertion depth of the puncturing member (e.g., asdescribed in further detail with reference to needle assembly 3200). Toinitiate injection (i.e., to move the injector assembly 2100 to thefifth configuration), the user can then exert a force on the engagementsurface 2121 of the actuating member 2120 in the direction shown by thearrow D. This urges the engagement protrusion 2122 to slide in the slot2117 distally to the user into the housing 2110 and engage theengagement surface 2132 of the pawl 2130. The engagement protrusion 2122can urge the pawl 2130 to rotate about the protrusions 2137, such thebiasing portion 2136 is biased and the latch 2134 disengages from theengagement portion 2322 of the actuator 2320. The biasing member 2146exerts a force on the engagement portion 2322 of the actuator 2320 andurges the actuator 2320 to displace proximally relative to themedicament containment chamber 2310. Thus, the plunger portion 2324 ofthe actuator slides an injection distance within the internal volume2316 of the medicament containment chamber 2310 and expels themedicament into the eye via the puncturing member. The housing 2110and/or the medicament containment chamber 2310 can be configured toprevent the housing 2110 from displacing distally relative to themedicament containment chamber 2310 in the fifth state. For example, insome embodiments, the flange 2313 of the medicament containment chamber2310 and/or an inner surface of the housing 2110 can have a highfriction surface. The flange 2313 and the inner surface of the housing2110 can contact each other to yield a high friction interface which canprevent the housing 2110 from displacing distally relative to themedicament containment chamber 2310 in the fifth state. In someembodiments, notches, grooves, indents, or any other features can bedefined in the internal volume of the housing 2110, and/or the flange2313. In some embodiments, a locking mechanism, for example, a twistlock mechanism, a push pin, a latch, a ledge, or any other suitablelocking mechanism can be included in the housing 2110. In suchembodiments, the user can engage the locking mechanism (e.g., twist thehousing 2110 relative to the medicament containment chamber 2310,depress a pin, etc.) such that the housing 2110 can be prevented fromdisplacing distally relative to the medicament containment chamber 2310in the fifth state. In this manner, the force exerted by the biasingmember 2146 is applied to move the actuator (or actuation rod) 2320distally relative to (and/or within) the medicament containment chamber2310, as opposed to being applied to move the entirety of the medicamentcontainment chamber 2310 relative to the housing 2110.

In some embodiments, the injector assembly 2100 can be used as aninjection-assist assembly to enable a user to inject the medicament intoa desired tissue of the eye, for example, the SCS. In such embodiments,the biasing member 2146 can be configured to exert a predetermined forceon the actuator 2320, for example a force of less than about 6N, lessthan about 5 N, less than about 4N, less than about 3 N, or less thanabout 2 N, inclusive of all ranges therebetween. The force can besufficient to expel the medicament from the medicament containmentchamber 2310 when the backpressure, existing or applied at an outlet ofthe puncturing member, is below a certain threshold. As described beforeherein, different layers of the eye can have different densities, forexample, the sclera is much denser then the SCS. Therefore, a puncturingmember inserted into the sclera will experience a much higherbackpressure than a puncturing member near or within the SCS. Thebiasing member 2146 can be configured to exert a force, which is onlysufficient to overcome the backpressure experienced in the target layer,for example, the SCS, but is not sufficient to overcome the backpressureof any other layer, for example, the sclera. In this manner, the biasingmember 2146 urges the actuator 2320 to expel the medicament only intothe target layer, for example, the SCS. The backpressure experienced bythe actuator can vary based on the medicament used, the size of thepuncturing member, the target ocular tissue layer, and/or thickness ofthe target layer. If the force delivered by the biasing member 2146 istoo high, injection can occur in the incorrect target layer, forexample, the sclera. Conversely, if the biasing force is too small,injection might not occur even when the outlet of the puncturing memberis within or near the target layer, for example, the SCS. To overcomethis, the biasing member 2146 can be tailored based on the medicamentused, the needle size, the size of the medicament containment chamber2310, the actuator 230, and/or target layer. In some embodiments, theactuator 2320 and the medicament containment chamber 2310 can becollectively configured such that the force exerted by the biasingmember 2146 produces an injection pressure within the internal volume2316 of the medicament containment chamber 2310 of between about 100 kPaand about 500 kPa. For example, the system 2000 can be configured suchthat the same injection pressure is produced within the medicamentcontainment chamber 2310, regardless of the size (e.g., diameter orotherwise cross-section) of the medicament containment chamber 2310and/or the actuator 2320, the material of the actuator 2320 or themedicament containment chamber 2310, the volume of the medicament, theviscosity of the medicament, and/or the size of the puncture member. Insome embodiments, the pressure produced in the medicament containmentchamber 2310 can be about 100 kPa, 110 kPa, 120 kPa, 130 kPa, 140 kPa,150 kPa, 160 kPa, 170 kPa, 180 kPa, 190 kPa, 200 kPa, 220 kPa, 240 kPa,260 kPa, 280 kPa, 300 kPa, 320 kPa, 340 kPa, 360 kPa, 380 kPa, 400 kPa,420 kPa, 440 kPa, 460 kPa, or about 480 kPa, inclusive of all ranges andvalues therebetween.

Furthermore, in some embodiments, the injector assembly 2100 can also beused to inform the user when the puncturing member is within or near thetarget layer. For example, the housing 2110 can be transparent such thatthe user can see the actuator 2320 and/or the medicament containmentchamber 2310. The user can insert the puncturing member into the eye andengage the actuating member 2120 such that the latch 2134 disengages theengagement portion 2322 of the actuator 2320. If the puncturing memberis within or near the target layer, for example, the SCS, the biasingmember 2146 overcomes the backpressure exerted by the target layer anddisplaces the actuator 2320 to move the injection distance and initiateinjection of the medicament into the target layer. The user can visiblyobserve the actuator 2320 and/or the plug 2328 displacing within thehousing 2110 and can be informed that the puncturing member is within orotherwise near the target layer, for example, the SCS. If the puncturingmember is in a layer other than the target layer, for example, thesclera, the biasing member 2146 will not overcome the backpressure ofthe other layer and the actuator 2320 will not displace proximallyrelative to the medicament containment chamber 2310. This can inform theuser that the puncturing member is not within or near the target layer.The user can then manipulate the puncturing member to reach within ornear the target layer and initiate injection of the medicament. In someembodiments, any other communication mechanism, for example, audiblealarm, LED light, a message, a display, a tactile alert, or any othercommunication mechanism can be used to inform the user about thelocation of the puncturing member. In some embodiments, the biasingmember 2146 can be configured to exert a force sufficient to expelsubstantially all of the medicament into the target layer, for example,the SCS. In some embodiments, the biasing member 2146 can be configuredto exert a force sufficient to initiate injection but not enough toexpel all of the medicament into the target layer. In such embodiments,the injection distance can be a first injection distance. Once theinjection is initiated, the user can then move the injection assembly2100 and thereby the actuator 2320 a second injection distanceproximally relative to the medicament containment chamber 2310. In thismanner, the remaining medicament can be delivered to the target layer ofthe eye.

FIG. 17 shows a schematic flow diagram of a method 200 of delivering amedicament to a target layer of a target tissue (or at a predetermineddistance within the target tissue) using a medical injector thatincludes an injection assembly. The method 200 includes inserting adistal tip of a needle of a medical injector (e.g., the system 100,1000, 2000, or any other system described herein) a first distance intoa target tissue, at 202. The needle can include any suitable needle, forexample, the needle 140 or any other needle described herein. Themedical injector includes a medicament container (e.g., the medicamentcontainer 130, 1310, 2310, or any other medicament container describedherein) and an injection assembly (e.g., the injection assembly 111,2100, or any other injection assembly described herein. The medicamentcontainer is in fluid communication with the needle. The injectionassembly includes an actuation rod (e.g., the actuation rod 120, theactuator 2320, or any other actuator described herein) and an energystorage member (e.g., the energy storage member 146, 2146, or any otherenergy storage member described herein). The energy storage member isconfigured to produce a force on a proximal end portion of the actuationrod.

The method 200 further includes releasing the actuation rod of theinjection assembly allowing a distal end portion of the actuation rod tomove within the medicament container in response to the force, at 204.For example, a proximal end portion of the actuation rod can be securedor otherwise engaged by a release member, for example, a pawl (e.g., thepawl 2130) or any other release member described herein. The releasemember can, for example, be moved from a first position in which theactuation rod is secured to a second position in which the actuation rodis released. As described herein, in certain situations the force willbe insufficient to overcome the viscous forces, tissue backpressure,frictional losses or the like within the fluid delivery path defined bythe medicament container, the needle and the target tissue when theneedle at the first distance within the tissue. Thus, the actuation rodmay not move, or may move less than a threshold “injection distance.”

Accordingly, the distal tip of the needle included in the medicalinjector can be inserted, after the releasing, a second distance greaterthan the first distance into the target tissue (e.g., the ocular tissueof an eye) if the distal end portion of the actuation rod moves lessthan a threshold injection distance within the medicament container inresponse to the force, at 206. The injection distance can be a distancethat the distal end portion of the actuation rod moves within themedicament container after the releasing. In some embodiments, theinjection distance is less than about 1 cm. In this manner, the lack ofmovement and/or the limited movement of the actuation rod in operation204 provides an indication to the user that additional movement and/orrepositioning of the needle tip is desirable. Conversely, when thedistal end portion of the actuation rod moves through the injectiondistance within the medicament container, the user is aware that theneedle tip is in a suitable region of the target tissue.

In some embodiments, the distal end portion of the actuation rod canmove a first injection distance within the medicament container inresponse to the force, for example, to deliver a portion of themedicament to the target tissue, for example, the SCS. In suchembodiments, the method 200 can further include moving the injectionassembly relative to the medicament container to move the distal endportion of the actuation rod a second injection distance greater thanthe first injection distance within the medicament container 208. Forexample, the force can move the actuation rod the first injectiondistance once the distal tip of the needle is disposed within or near adesired region of the target tissue. This can indicate to a user thatthe distal tip of the needle is disposed within or near a desired regionof the target tissue. The actuation rod can then be moved proximallyrelative to the medicament container such that the actuation rod movesthe second injection distance within the medicament container. In someembodiments, the distal end portion of the actuation rod can be movedthe second injection distance manually by a user, for example, by movingthe housing proximally to the medicament container. In otherembodiments, the medical injector can include an automated deliverymechanism (e.g., a mechanical actuator, a pump, or any other suitableautomated delivery mechanism) configured to move the actuation rod thesecond injection distance and deliver substantially all of themedicament to the target tissue.

In some embodiments, the target tissue can be an eye. In suchembodiments, the inserting of the distal tip of the needle of themedical injector the second distance into the eye includes inserting atleast a portion of the distal tip into a suprachoroidal space of theeye. In some embodiments, inserting the distal tip of needle of themedical injector the second distance includes contacting a surface ofthe eye with a hub coupled to the needle. The hub can include the hub7270, 8270, 9270 or any other hub described herein in further detailbelow.

FIG. 18 shows a schematic flow diagram of a method 300 for delivering amedicament to a target layer of a target tissue or a predetermineddistance within the target tissue using a medical injector that includesan injection assembly. The method 300 includes inserting a distal tip ofa needle of a medical injector (e.g., the medical injector 100, 1000,2000 or any other medical injector described herein, into a medicamentcontained within a medicament vial 302. The medicament vial can be anysuitable commercially available medicament vial, bottle, container, orany other vessel housing a medicament. The medicament can include anysuitable medicament (e.g., VEGF, a VEGF inhibitor, a combinationthereof, or any other medicament described herein) formulated to bedelivered to a target tissue (e.g., the SCS of the eye). The medicalinjector includes a medicament container and an injection assembly, andis in fluidic communication with the needle. The injection assemblyincludes an actuation rod, and energy storage member, a release memberand an actuation member. In some embodiments, the injection assembly andthe components of the injection assembly described herein can besubstantially similar to the components of the injection assembly 111,2100, or any other injection assembly described herein. The energystorage member (e.g., a spring, a compressed gas container, or acontainer containing a propellant) is configured to produce a force on aproximal end portion of the actuation rod. The proximal end portion ofthe actuation rod can be engaged and secured by the release member. Forexample, the securing can lock the movement of the actuation rod withrespect to a housing within which the actuation rod, the injectionassembly, and/or at least a portion of the medicament container isdisposed. Said another way, the securing of the proximal end portion ofthe actuation rod by the release member prevents a distal end portion ofthe actuation rod from moving relative to the housing. Furthermore, anymovement of the housing relative to the medicament container also urgesthe distal end portion of the actuation rod to move within themedicament container.

Next, the method includes moving the distal end portion of the actuationrod distally relative to the medicament container to draw a volume ofthe medicament within the medicament container, at 304. Then, themedicament container is moved proximally relative to the actuation rodto expel a volume of the medicament from the distal tip of the needleand leave a dose volume of the medicament remaining in the medicamentcontainer, at 306. Said another way, any excess medicament drawn intothe medicament container can be expelled from the medicament containerby moving the medicament container proximally relative to the actuationrod.

The distal tip of the needle is then inserted a first distance into atarget tissue, for example, an ocular tissue, at 308. The actuationmember is activated (e.g., by a user) to disengage the release memberform the actuation rod, thereby releasing the proximal end portion ofthe actuation rod. This allows the distal end portion of the actuationrod to move a first injection distance within the medicament containerin response to the force produced by the energy storage member, at 310.As described herein, the actuation rod will move the first injectiondistance (or a great amount) when the needle tip is disposed within adesired region of the target tissue. Conversely, when the needle tip isnot disposed within a desired region of the target tissue, the forceproduced by the energy storage member is insufficient to move theactuation rod by the first injection distance.

The method 300 then includes determining if the actuation rod has moveda threshold injection distance, at 312, for example, the first injectiondistance. For example, a user can visually observe if the distal endportion of the actuation rod moved within the medicament container ornot (e.g., through a transparent housing of the medical injector). Ifthe actuation rod did not move, the distal tip of the needle of themedical injector is inserted, after the releasing, a second distancegreater than the first distance into the target tissue, at 314. In thismanner, the user can reposition the needle tip (e.g., by insertingfurther, or removing from the tissue) in response to the indicationproduced by the actuation rod.

For example, the first distance can correspond to a sclera of the eye,which has a backpressure that, in conjunction with the frictionallosses, viscous loses and the like via the fluid flow path, cannot beovercome by the force of the energy storage member. Thus, the actuationmember does move the first injection distance to deliver at least aportion of the medicament into the sclera. The distal tip of the needleis then moved the second distance which can correspond to a targetregion of the target tissue, for example, the SCS. The method thenreturns to operation 312 to determine if the actuation rod has moved thefirst injection distance. If the actuation rod has moved the firstinjection distance, this confirms that the distal tip of the needle isdisposed in the desired target region. For example, the target regioncan be SCS, which has a lower backpressure than that produced by thesclera. The force exerted by the energy storage member can be configuredto overcome this backpressure such that the distal end portion of theactuation rod can be moved the first injection distance and deliver atleast a portion of the medicament into the target tissue via the distaltip of the needle. In some embodiments, the force can be between about 2N to about 6 N. Finally, the distal end portion of the actuation rod ismoved a second injection distance until substantially all of themedicament is expelled from the medicament container into the targettissue (e.g., the SCS) at 316, via the distal tip of the needle. Forexample, the user can manually move the distal end portion of theactuation rod, or use any suitable actuation mechanism included in themedical injector to move the distal end portion of the actuator thesecond injection distance.

In some embodiments, a medical injector can include a needle assemblyconfigured to adjust the length of a needle, for example, to adjust adistance the needle penetrates into a target tissue, for example, anocular tissue. FIGS. 19 and 20 are schematic illustration of a medicalinjector 400 in a first configuration and a second configuration,according to an embodiment. The medical injector 400 includes a housing410, an actuator rod 420, a medicament container 430, a needle 440, andan adjustment member 423. Optionally, the medical injector 400 can alsoinclude a hub 470 coupled to the housing 410. The housing 410 isconfigured to receive a portion of the medicament container 430. Thehousing 410 can include any suitable housing, for example, the housing3210, or any other housing described herein with respect to a needleassembly.

The needle 440 can be any suitable puncture member configured topuncture a target tissue. For example, the needle 440 can be amicroneedle configured to puncture ocular tissue. In some embodiments,the needle 440 can be a 32-gauge microneedle or a 34-gauge microneedle.In some embodiments, such a microneedle can be substantially similar toor the same as the microneedles described in the '009 PCT applicationincorporated by reference above. In some embodiments, the shape and/orsize of the needle 440 can correspond, at least partially, with at leasta portion of a target tissue. For example, in some embodiments, thelength of the needle 440 can correspond with a thickness of a portion ofocular tissue such that when the needle 440 is inserted into the oculartissue, at least a portion of the needle 440 is disposed within thesclera or suprachoroidal space of the eye, as described in furtherdetail herein. The needle 440 defines a lumen 441 that extends through aproximal end portion 443 and a distal end portion 442 of the needle 440.The distal end portion 442 of the needle 440 can include a bevel or asharpened tip configured to puncture a target tissue. At least a portionof the proximal end portion of the needle 440 can be disposed in apassageway defined by the hub 470, as described herein.

The medicament container 430 of the medical injector 400 has a proximalend portion 432 and a distal end portion 434. The medicament container430 defines an inner volume 436 that can store, house, and/or otherwisecontain a substance (e.g., a medicament, a prophylactic agent, atherapeutic agent, and/or a diagnostic agent). For example, in someembodiments, a cartridge or the like containing a drug formulation canbe disposed within the inner volume 436 of the medicament container 430.In other embodiments, a drug formulation can be disposed directly withinthe inner volume 436 (e.g., without a cartridge or other intermediatereservoir). In some embodiments, the inner volume 436 can contain a drugformulation with a volume of about 0.5 mL or less. In other embodiments,the inner volume 436 can contain a drug formulation with a volume ofabout 0.1 mL. In still other embodiments, the inner volume 436 cancontain a drug formulation with a volume greater the about 0.5 mL. Insome embodiments, the medicament container 430 can be substantiallysimilar to the medicament container 1310, 2310, 3310, or any othermedicament container described herein.

The proximal end portion 432 of the medicament container 430 issubstantially open to receive the actuation rod 420. More specifically,a distal end portion 424 of the actuation rod 420 is disposed within theinner volume 436 and can be moved between a first position (e.g., aproximal position) and a second position (e.g., a distal position). Saidanother way, the distal end portion 424 of the actuation rod 420 canmove an injection distance within the inner volume 426. A sealing membersuch as, for example, a plug can be coupled to the distal end portion424 of the actuation rod 420. The sealing member can be configured toform a friction fit with one or more surfaces of the medicamentcontainer 430 that define the inner volume 436. In this manner, the sealmember and the medicament container 430 can form a fluidic seal thatsubstantially isolates a portion of the inner volume 436 that is distalto the seal member from a portion of the inner volume 436 that isproximal to the seal member. Said another way, the medicament container430 and the actuation rod 420 form at least a portion of a syringe.

In some embodiments, the distal end portion 434 of the medicamentcontainer 430 is physically and fluidically coupled to the hub 470. Forexample, in some embodiments, the hub 470 and the distal end portion 434of the medicament container 430 can form a press fit, a snap fit, athreaded coupling, and/or the like. In other embodiments, the hub 470can be monolithically formed with the medicament container 430. The hub470 can define a passageway configured to receive the needle 440therethrough such that the distal end portion 442 of the needle extendspast a distal end surface of the hub 470 by a distance, for example, afirst distance d₁ (see e.g., FIG. 19 ) that can change, for example, toa second distance d₂ (see e.g., FIG. 20 ) or any other distance, whenthe needle is moved through a plurality of discrete increments along thelongitudinal axis of the housing 410, as described herein. In someembodiments, the hub 470 can also be configured to limit movement of theadjustment member 422 within the housing 410.

A proximal end portion of the adjustment member 423 is configured to becoupled to the medicament container 430. The coupling can be performedusing any suitable coupling mechanism, for example, a Luer lock,threads, snap-fit, friction-fit, or any other suitable couplingmechanism. A distal end portion of the adjustment member 423 is coupledto the needle 440, for example, to the proximal end portion 443 of theneedle 440. In some embodiments, the adjustment member 423 can define alumen configured to place the medicament container 430 in fluidcommunication with the needle 440. In some embodiments, the proximal endportion of the adjustment member 423 can also include a flangeconfigured to be removably coupled to the medicament container 430. Theadjustment member 420 is configured to transition between a firstconfiguration (FIG. 19 ) and a second configuration (FIG. 20 ) to adjustthe distance that the distal end portion 442 of the needle 440 extendspast the distal end surface of the hub 470. For example, the adjustmentmember 423 can be movably disposed within the housing 410 such that whenthe adjustment member 423 is rotated relative to the housing 410, theneedle 440 is moved through a plurality of discrete increments along alongitudinal axis of the housing 410. In this manner, the adjustmentmember 423 can adjust the effective length of the needle 440 in theplurality of discrete increments. Said another way, the adjustmentmember 423 can allow digital adjustment of the length of the needle 440.While not shown, in some embodiments, the adjustment member 423 and/orthe housing 410 can include a plurality of detents. The detents can beconfigured such that each increment from the plurality of discreteincrements is associated with a corresponding detent from the pluralityof detents defined by at least one of the adjustment member 423 and/orthe housing 410. For example, the housing 410 can include a protrusionconfigured to be removably disposed within each detent from theplurality of detents when the adjustment member 423 is rotated relativeto the housing 410 to move the needle 440 through the plurality ofdiscrete increments. As another example, in some embodiments, a bearingcan be coupled within the housing 410 and configured to be removablydisposed within each detent from the plurality of detents when theadjustment member 422 is rotated within the housing 410 to move theneedle through the plurality of discrete increments. In suchembodiments, a bias member can also be disposed in the housing 410 andconfigured to maintain the bearing within a detent from the plurality ofdetents. In some embodiments, the medical injector 400 can also includea lock member, for example, a lock, a latch, a tab, a rod, or any othersuitable lock member removably coupled to the housing 410. The lockmember can be configured to engage the adjustment member 423 to limitmovement of the adjustment member 423 relative to the housing 410. Insome embodiments, at least a portion of the adjustment member 423 caninclude an indication portion, for example, a portion including aplurality of markings. The markings can be configured to indicate adistance that the needle 440 extends beyond the housing 410 (e.g.,extends beyond the distal end surface of the hub 470). In suchembodiments, the housing 410 can define a window such that theindication portion is visible through the window. For example, a usercan view the indication portion through the window to determine thedistance that the needle 440 extends beyond the housing 410 and estimatean insertion depth of the distal end 442 of the needle 440 into a targettissue.

As shown in FIG. 19 , in the first configuration of the adjustmentmember 423, the distal end portion 442 of the needle 440 can be spacedapart from a distal end surface of the hub 470 by a first distance d₁.The adjustment member 423 can then be moved into a second configurationby moving (e.g., rotating, translating or rotating and translating) theadjustment member 423 within the housing 410. This urges the needle 440to move in a discrete increment such that distal end portion 442 of theneedle 440 extends a second distance d₂, larger than d₁, beyond thedistal end surface of the hub 470, as shown in FIG. 20 . In this manner,a length of the needle 440 extending beyond the distal edge surface ofthe hub 470 can be adjusted.

In use, an operator (e.g., a doctor, technician, nurse, physician,ophthalmologist, etc.) can manipulate the delivery device 400 to insertthe needle 440 into, for example, an ocular tissue. In this manner, thedistal end portion 442 of the needle 440 can be advanced within thetarget tissue to pierce the sclera and place the hub 470 in contact withan outer surface of the sclera. Moreover, with the adjustment member 422in the first configuration, the first distance d₁ between the distal endsurface of the hub 470 and the distal end portion 442 of the needle 440can substantially correspond to the thickness of the sclera. In thismanner, a distal tip of the needle 440 can be disposed within the sclera(e.g., the sclera 20 of the eye 10 in FIG. 1 ).

The adjustment member 423 can be transitioned from the firstconfiguration to the second configuration by moving, translating orrotating the adjustment member 423 within the housing 410. In someembodiments, the moving of the adjustment member 423 can be performed bymoving (e.g., rotating) the medicament container 430 relative to thehousing 410. This can increase the distance between the distal endsurface of the hub 470 and the distal end portion 423 of the needle 440from the first distance d₁ to the second distance d₂ (as describedabove). In this manner, when the adjustment member 422 is in the secondconfiguration, the distal tip of the needle 440 can be moved furtherproximally relative to the ocular tissue to place the lumen 441 of theneedle 440 in fluid communication with the suprachoroidal space (e.g.,the suprachoroidal space 36 of the eye 10 in FIG. 1 ). With the lumen441 of the needle 440 in fluid communication with the suprachoroidalspace, the actuation rod 420 can be moved relative to the medicamentcontainer 430 from its first position to its second position. With thedistal end portion 424 of the actuation rod 420 forming a substantiallyfluidic seal (i.e., a substantially hermetic seal) with an inner surfaceof the medicament container 430, the movement of the actuation rod 420to its second position expels the drug formulation (contained within theinner volume of the medicament container 430) through the lumen 441 ofthe needle 440. Thus, the medical injector 400 can deliver the drugformulation to the SCS of the eye and the drug formulation can flowwithin the suprachoroidal space to be delivered to, for example, theposterior region of the eye.

By adjusting the distance between the distal edge surface of the hub 470and the distal end portion 442 of the needle 440 in discrete incrementsusing the adjustment member 423, the distal end portion 442 of theneedle 440 can be placed within the SCS with more accuracy and precisionthan would otherwise be achieved with a fixed distance therebetween. Forexample, in some instances, the adjustment member 423 can be arrangedsuch that the first distance d₁ between the distal end surface of thehub 470 and the distal end portion 442 of the needle 440 is less thanthe thickness of the sclera. Thus, the adjustment member 423 can bemoved to the second configuration to increase the distance between thedistal edge surface of the hub 470 and the distal end portion 442 of theneedle 440 (e.g., to the second distance d₂) that is greater than thethickness of the sclera, thereby placing the distal end portion 442 ofthe needle 440 in contact with the SCS. Moreover, the second distance d₂can be less than a combined thickness of the sclera and the SCS suchthat when the adjustment member 423 is moved to the secondconfiguration, the distal end portion 442 of the needle 440 does notpierce the choroid (e.g., the choroid 28 of the eye 10 in FIG. 1 ).

The arrangement of the adjustment member 423, the needle 440, and thehub 470 allows for control of the effective length of the needle 440.Accordingly, the medical injector 400 can be used for proceduresinvolving different portions of a target tissue (e.g., the eye) havingdifferent thicknesses. Moreover, control over the effective length ofthe needle 440, as described herein, allows the medical injector 400 tobe used on a variety of patients having a range of anatomicaldifferences (e.g., the device can be used in adult applications andpediatric applications).

The transition of the adjustment member 423 (and any of the needleassemblies described herein) between the first configuration and thesecond configuration can be performed at any suitable time before and/orduring a procedure. For example, in some embodiments, the adjustmentmember 423 can be transitioned to the second configuration to set and/oradjust the effective length of the needle 440 before insertion of theneedle 440 into the target tissue. The desired effective length of theneedle 440 in such embodiments can be based on the known thickness ofthe sclera based on pre-operation measurements or the like. In otherembodiments, however, the adjustment member 422 can be transitioned tothe second configuration after the needle 440 has been inserted into thetarget tissue. In this manner, the adjustment member 422 can provide theoperator with a mechanism for adjusting the effective length of theneedle 440 in discrete increments during the procedure (e.g., based ontactile feedback, optical feedback or the like).

The medical injector 400 is shown in FIGS. 19-20 by way of example toprovide context to the proceeding discussion. In this manner and forsimplicity, only portions of a medical injector according to specificembodiments are shown. It should be understood that any of theembodiments described herein can be disposed in a similar arrangement asdescribed above with reference to FIGS. 19-20 . Moreover, while thedelivery device 400 is shown and described with reference to FIGS. 19-20as having a particular arrangement, the embodiments described herein canbe used with any suitable delivery mechanism or device.

In some embodiments, a system for injecting a medicament into oculartissue can include a needle assembly configured to perform any of thefunctions described herein. In other embodiments, a needle assembly canbe configured to adjust the length and/or insertion depth of the needle.Referring now to FIGS. 21-33 a system 3000 can include at least ahousing 3110, a medicament containment chamber 3310, an actuator 3320,and a needle assembly 3200. The needle assembly 3200 can be configuredto adjust a length of a puncturing member 3240 (also referred to as adelivery member and/or a needle) included in the needle assembly 3200,as described herein. The system 3000 can be configured to deliver amedicament to a layer or region of an eye of patient, for example, tothe SCS of the eye.

The housing 3110 can include any of the housings described herein and isconfigured to receive at least a portion of the medicament containmentchamber 3310. In some embodiments, the housing 3110 can be substantiallysimilar to the housing 1110 described with respect to the system 1000.In such embodiments, the housing 3110 can be configured for manualmanipulation of the actuator 3320 to inject the medicament. In someembodiments, an injector assembly can be disposed in the housing 3110.The injector assembly can be substantially similar to the injectorassembly 2100 or any other injector assembly described herein, and istherefore not described in further detail herein.

The medicament containment chamber 3310 defines an internal volume 3316configured to house a medicament (e.g., a VEGF, a VEGF inhibitor,triamcinolone acetonide, any other medicament described herein, or acombination thereof). The medicament containment chamber 3310 includesan engagement portion disposed inside the internal volume defined by thehousing 3110. The medicament containment chamber 3310 also includes adelivery portion disposed outside the internal volume defined by thehousing 3110 and coupled to the needle assembly 3200. The medicamentcontainment chamber 3310 can be substantially similar to the medicamentcontainment chamber 1310, 2310 or any other medicament containmentchamber described herein, and is therefore not described in furtherdetail herein.

The actuator 3320 includes an engagement portion and a plunger portion.The plunger portion is slidably disposed inside the internal volume 3316defined by the medicament containment chamber 3310 and is configured todraw the medicament into or expel the medicament from the internalvolume 3316 defined by the medicament containment chamber 3310. Theactuator 3320 can be substantially similar to the actuator 1320, 2320 orany other actuator described herein, and is therefore not described infurther detail herein.

As shown in FIG. 22 , the needle assembly 3200 includes a housing 3210,a bearing (or lock ball) 3220, an adjustment member 3230, a puncturingmember 3240, a lead screw 3242, a bushing 3250, a locking pin 3260, anda hub 3270. The needle assembly 3200 is configured to enable lineartranslation of the puncturing member 3240 in fixed and/or discreteincrements to allow a user to insert the puncturing member to a desireddepth within the eye, for example, insertion to the depth of the SCS.

The housing 3210 (FIGS. 23A-C, FIGS. 32 and 33 ) includes a proximalportion 3211 and a distal portion 3212. The housing 3210 can besubstantially cylindrical in shape and tapers towards the distal portion3212. The housing 3210 defines an internal 3213 volume within which thebearing 3220, the adjustment member 3230, at least a portion of thepuncturing member 3240, the lead screw 3242, the bushing 3250, and atleast a portion of the locking pin 3260 can be disposed. The internalvolume 3213 defines a substantially circular cross-section to allow oneor more components, for example, the adjustment member 3230 and/or thelead screw 3242 to rotate about a longitudinal axis A_(L) of the system3000 within the internal volume 3213. A delivery portion of themedicament containment chamber 3310 can also be disposed in the internalvolume 3213. The distal portion 3212 of the housing 3210 is configuredto receive a proximal end 3272 of the hub 3270 (see FIGS. 31A-31C) orany other hub described herein. Coupling features can be included in thedistal portion 3212 to removably or fixedly couple the proximal end 3272of the hub 3270. Suitable coupling features can include, for example, afriction fit mechanism, threads, a Luer assembly, adhesive, lock, latch,groove, indents, detents, a snap-fit mechanism, or any other suitablecoupling mechanism. A multiplicity of ridges 3214 are disposed on anouter surface of the housing 3210. The ridges 3214 can be configured toallow the user to ergonomically grip the housing 3210, for example, whenperforming an injection of a medicament into the eye. A window 3216 isdefined in the housing 3210. The window 3216 is configured to align withan intermediate portion 3233 of the adjustment member 3230, such thatthe user can see a set of markings 3236 defined on an outer surface ofthe intermediate portion 3233. The markings 3236 can indicate a lengthof the puncturing member 3240 protruding from a distal end 3274 of thehub 3270, which can correspond to the insertion depth of the puncturingmember 3240 (e.g., a distance that a distal tip of the puncturing member3240 traverses into the ocular tissue). A cavity 3218 is defined in thehousing 3210. The cavity 3218 is configured to receive the bearing 3220,a biasing member 3221 and a plug 3222, as described in further detailherein. A set of through holes 3219 are defined in the sidewall of thehousing 3210. The locking pin 3260 is inserted through the through holes3219, such that the locking pin passes through the internal volume 3213defined by the housing 3210, and at least a portion of the locking pin3260 is disposed within the internal volume 3213.

The bearing (or lock ball) 3220 is disposed in the cavity 3218 of thehousing 3210. The bearing can be any suitable bearing, for example, ametallic, plastic, or wooden bearing, a contoured cylindrical member, orany other suitable bearing. A first end of the biasing member 3221 iscoupled and/or engaged with to the bearing 3220, and a second end of thebiasing member 3221 is coupled to the plug 3222. The biasing member 3221can include a spring, for example, helical, compression, extension,spring washers, Belleville washers, tapered, any other type of spring,or any other suitable biasing member. At least a portion of the plug3222 (FIGS. 24A-B) is disposed within the cavity such that the plug 3222secures the biasing member 3221 and the bearing 3220 inside the cavity3218. The plug 3222 can include a dome shaped surface with roundededges. In some embodiments, the plug 3222 can be fixedly coupled to thecavity 3218, for example, via adhesives. In some embodiments, the plug3222 can be removably coupled to the cavity 3218 using a suitablecoupling mechanism such as, for example, friction-fit, threads, grooves,indents, detents, any other suitable coupling mechanism or combinationthereof. The plug 3222 can be configured to exert a force on and/ormaintain a position of the biasing member 3221 such that the biasingmember 3221 exerts a force against the bearing 3220. The bearing (orlock ball) 3220 is configured to engage at least one of a set of detents3235 disposed on a distal portion 3234 of the adjustment member 3230.The biasing member 3221 biases the bearing 3220 inward relative to thedetents 3235 such that the bearing 3220 prevents the adjustment member3230 from rotating freely relative to the housing 3210 about thelongitudinal axis A_(L) of the system 3000. In this manner, the bearing3220 allows a digital length adjustment of a length of the puncturingmember 3240, as described in further detail herein. Similarly stated,the engagement of the bearing 3220 in the detents 3235 allows therotational position of the adjustment member 3230 (and thus theeffective length of the puncturing member 3240) to be adjusted indiscrete increments.

The adjustment member 3230 (FIGS. 25 , FIGS. 26A-B, FIG. 33 ) includes aproximal portion 3232, an intermediate portion 3233, and a distalportion 3234. The proximal portion 3232 is configured to couple to adelivery portion of the medicament containment chamber 3310. Theproximal portion 3232 can include coupling features, for example, Luerlock connectors, threads, grooves, notches, indents, snap-fit,friction-fit, lock, latch, any other suitable coupling features orcombination thereof. In this manner, the distal end portion of themedicament containment chamber 3310 can be coupled to the adjustmentmember 3230. In some embodiments, the delivery portion of the medicamentcontainment chamber 3310 can be fixedly coupled to the proximal portion3232, for example, by an adhesive. In other embodiments, the deliveryportion of the medicament containment chamber 3310 can be removablycoupled to the proximal portion 3232, for example, to allow the user toreplace the medicament containment chamber 3310 to reuse the needleassembly 3200. In some embodiments, a locking feature (not shown), forexample, a lock, a latch, or a friction fit, can be included in theproximal portion 3232. The locking feature can be configured to preventuncoupling of the delivery portion of the medicament containment chamber3310 from the proximal portion 3232 of the adjustment member 3230 due toa rotation of the medicament containment chamber 3310 (e.g., because ofa rotation of the housing 3310 by the user). For example, a user canrotate the housing 3310 about the longitudinal axis A_(L) of the system3000 urging the medicament containment chamber 3310 and thereby, theadjustment member 3230 to also rotate about the longitudinal axis A_(L).In this manner, the adjustment member 3230 can be configured to vary thelength of the puncturing member 3240 protruding through the distal endof the 3274 of the hub 3270, as described in further detail herein.

The intermediate portion 3233 of the adjustment member 3230 includesmarkings 3236 corresponding to the length of the puncturing member 3240protruding through distal end 3274 the hub 3270. The intermediateportion 3233 is aligned with the window 3216 included in the housing3210 such that the user can see the markings 3236 through the window3216 and determine the protruding length of the puncturing member 3240.This can, for example, indicate the insertion depth of the puncturingmember 3240 into the eye. In some embodiments, the markings 3236 canindicate a length in the range of about 850 microns, 950 microns, 1050microns, 1150 microns, or about 1250 microns. In such embodiments, thelength interval can be about 100 microns. The intermediate portion 3233also includes a fluidic channel 3238 defined therethrough. The fluidiccannel 3238 can be in fluidic communication with the internal volume3316 of the medicament containment chamber 3310.

The distal portion 3234 is fixedly coupled to a proximal portion 3244 ofthe lead screw 3242. For example, the proximal portion 3244 of the leadscrew 3242 can be welded, bonded, adhered, bolted, riveted, or fixedlymounted using any other coupling mechanism to the distal portion 3234 ofthe adjustment member 3230. In this manner, a rotation of the adjustmentmember 3230 can also rotate the lead screw 3242 about the longitudinalaxis A_(L) of the system 3000. The set of detents 3235 are defined onthe outer surface of the distal portion 3234 and are configured to beengaged by the bearing 3220, as described herein. Although the leadscrew 3242 and the adjustment member 3230 are shown and described asbeing separate components that are joined together, in otherembodiments, the lead screw 3242 and the adjustment member 3230 can bemonolithically formed.

The lead screw 3242 (FIGS. 22, 25, 27A-B, 33) includes the proximalportion 3244 and a distal portion 3246. The proximal portion 3244 isfixedly coupled to distal portion 3234 of the adjustment member 3230, asdescribed herein. The distal portion 3246 is coupled to a proximal endof the puncturing member 3240 coupled thereto. The puncturing member3240 can be a needle (e.g., a 27 gauge, a 30 gauge, or even smallerneedle), or any other puncturing member described herein. The puncturingmember 3240 defines a lumen 3241 (FIG. 33 ) configured to fluidicallycommunicate the medicament to a target tissue of the eye, for example,the SCS. The puncturing member 3240 is fixedly coupled to the lead screw3242 by any suitable mechanism. In this manner, a rotation of theadjustment member 3230 and lead screw 3242 about the longitudinal axisA_(L), which causes a linear translation of the lead screw 3242 alongthe longitudinal axis A_(L), also urges the puncturing member 3240 torotate about or translate along the longitudinal axis A_(L),respectively. The lead screw 3242 defines a lumen 3247 therethrough. Thelumen 3247 is in fluidic communication with the fluidic channel 3238 ofthe adjustment member 3230 and the lumen 3241 of the puncturing member3240. Thus, the fluidic channel 3238 of the adjustment member 3230, andthe lumen 3247 of the lead screw 3242 provide a fluidic path for themedicament to be communicated between the internal volume 3316 of themedicament containment chamber 3310 and the lumen 3241 of the puncturingmember 3240, for example, delivered to a target layer (e.g., the SCS) ofthe eye.

At least a portion of the outer surface of the lead screw 3242, forexample, the distal portion 3246, includes threads 3248. The threads3248 are configured to mate with mating threads 3254 included in thebushing 3250. The bushing 3250 (FIGS. 22, 28A-C, FIG. 33 ) is fixedlydisposed inside the internal volume 3213 defined by the housing 3210.The bushing 3250 defines a lumen 3252 configured to receive the distalportion 3246 of the lead screw 3242 such that the threads 3248 of thelead screw 3242 are mated with the mating threads 3254 disposed alongthe surface of the lumen 3252 of the bushing 3250. Because the bushing3250 is fixedly disposed in the housing 3210, a rotation of theadjustment member 3230 and the lead screw 3242 relative to the housing3210 about the longitudinal axis A_(L) urges the lead screw 3242 to movelinearly relative to the housing 3210 along the longitudinal axis A_(L)of the system 3000. Each full rotation of the lead screw 3242 cancorrespond to a predetermined translation distance of the lead screw3242 and thereby, the puncturing member 3240, along the longitudinalaxis A_(L) of the system 3000. In this manner, the adjustment member3230 can be rotated (e.g., by rotating the housing 3110) to rotate thelead screw 3230 and thereby, advance or retract a predetermined lengthof the puncturing member 3240 from the distal end 3274 of the hub 3270.

The locking pin 3260 (FIG. 29 ) is coupled to a tab 3262. As shown inFIGS. 30A-C, the tab 3262 includes a cavity 3264 configured to receiveat least a portion of the locking pin 3260. In some embodiments, the tab3262 can be removably coupled to the locking pin 3260, for example via,threads, grooves, notches, indents, detents, friction fit, or coupledusing any other suitable coupling mechanism. In some embodiments, thetab 3262 can be fixedly coupled to the locking pin 3260, for example,via adhesives. At least a portion of the tab 3262 can be substantiallyflat. Although the locking pin 3260 is shown as being substantiallycylindrical, in other embodiments, the locking pin can define acircular, oval, square, rectangular, polygonal, or any other suitablecross section. The locking pin 3260 is configured to be inserted throughand/or within the through holes 3219 of the housing 3210, such that atleast a portion of the locking pin 3260 is disposed in the internalvolume 3213 defined by the housing 3210.

The locking pin 3260 is configured to be moved from a firstconfiguration (or position) and a second configuration (or position). Inthe first configuration, the locking pin 3260 is inserted through thethrough holes 3219 and at least a portion of the locking pin 3260 isdisposed in proximity of the intermediate portion 3233 of the adjustmentmember 3230. In the first configuration, the locking pin 3260 isconfigured to prevent a rotation of the adjustment member 3230 relativeto the housing 3210, and thereby, the lead screw 3242. Thus, when thelocking pin 3260 is in the first configuration, movement of thepuncturing member 3240 along the longitudinal axis A_(L) of the system3000 distally relative to the medicament containment chamber 3310, forexample, because of the rotation of the adjustment member 3260, islimited. In a second configuration, the user can pull the tab 3262 andthereby the locking pin 3260 out of the through holes 3219 and theinternal volume 3213. Thus, in the second configuration the adjustmentmember 3230 can be free to rotate relative to the housing 3210, and thusmove linearly along the longitudinal axis A_(L), for example, to advancea length of the puncturing member 3240 from a distal end 3274 of the hub3270. Said another way, the locking pin 3260 can serve as a safetymechanism to prevent accidental activation of the needle assembly 3200and prevent advancement of the puncturing member 3260 out of the distalend 3274 of the hub 3270.

The hub 3270 includes a proximal portion 3272 and a distal portion 3274.The proximal portion 3272 is configured to be coupled to the distalportion 3214 of the housing 3210 (or any other housing defined herein)using any suitable coupling mechanism, for example, friction-fit,threads, snap-fit, notches, grooves, indents, detents, any othersuitable coupling mechanism or combination thereof. The hub 3270 definesa lumen 3276 therethrough. At least a portion of the puncturing member3240 (or any other puncturing member described herein) can be disposedin the lumen 3276, and can be configured to advance through the lumen3276 out of the distal end 3274. The distal end 3274 of the hub 3270 issubstantially flat, and is configured to contact an outer surface of theconjunctiva of the eye. Although the hub 3270 is shown and described ashaving a flat distal end (or “contact”) surface, in some embodiments, adistal portion of a hub can define substantially convex or curvedsurface, as described in further detail herein.

In operation, the needle assembly 3200 is configured to allow a user toadjust a length of the puncturing member 3240 emerging from the distalend of the hub 3270. FIG. 32 shows a perspective view of the needleassembly 3200 and FIG. 33 shows a cross-section of the needle assembly3200 taken along the line 33-33. While shown as including the hub 3270,any other hub can be coupled to the distal end 3212 of the housing 3210,for example, the hub 7270, 8270, 9270, or any other hub describedherein. The proximal portion 3232 of the adjustment member 3230 can becoupled to the delivery portion 3314 of the medicament containmentchamber 3310. In a first configuration, a first length of the puncturingmember 3240 can be protruding from the distal end 5274 of the hub 5270,for example, about 850 microns. This information can be communicated tothe user via the markings 3236 visible to the user through the window3216. At least a portion of the bearing 3220 is disposed in a firstindent 3235 defined on the outer surface of the distal portion 3234 ofthe adjustment member 3230. The bearing 3220 is biased against the firstindent 3235 by the biasing member 3221, and prevents any inadvertentrotation of the adjustment member 3270, thus maintaining the position ofadjustment member 3230. In the first configuration, the puncturingmember 3240 can protrude a known distance from the distal end 3274 ofthe hub, for example a length of about 850 microns.

To enable actuation of the needle assembly 3200, the user can remove thelocking pin 3260 by pulling on the tab 3262 to remove the locking pin3260 from the housing 3210. The user then disposes the distal end 3274of the hub 3270 against the outer surface of the conjunctiva of the eye,which results in the initial length of the puncturing member 3240 beinginserted into the eye. Similarly stated, the user can apply a distalforce on the system 3000 such that a distal end of the puncturing member3240 pierces the conjunctiva and is disposed in an ocular tissue layerbelow the conjunctiva, for example, the sclera. The user can thendetermine, using any suitable technique, if a distal end of thepuncturing member 3240 is within or otherwise near a target layer, forexample, the SCS of the eye. In some embodiments, the user can determinethat the distal end of the puncturing member 3240 is not in a targetlayer of the eye, for example, the SCS. For example, in someembodiments, a relative thickness of the ocular tissue layers can beknown to the user via prior visualization techniques. In otherembodiments the system 3000 can include an injection assembly, forexample, the injection assembly 111, 2100, or any other injectionassembly described herein, which can be activated and thereby inform theuser that the distal end of the puncturing member 3240 is not in thetarget layer, as described before herein. More particularly, because theinjection assembly provides an “injection assist” force within apredetermined range, when the end of the puncturing member 3240 has notreached the SCS, actuation of the injection assembly will not result inmovement of the plug within the medicament containment chamber. Thus,the user will receive feedback that the puncturing member 3240 is not inthe target region (i.e., by not seeing any movement of the plug).

To move the needle assembly 3200 to a second configuration, the user canapply a first torque to rotate or otherwise twist the medicamentcontainment chamber 3310 such that the adjustment member 3230 rotatesrelative to the housing 3210 about the longitudinal axis A_(L). Thefirst torque can urge the bearing 3220 to slide out of the first indent3235 such that the adjustment member 3230 is free to rotate byapplication of a second torque substantially smaller than the firsttorque. The rotation of the adjustment member 3230 urges the lead screw3242 to also rotate in the bushing 3250. Since the bushing 3250 isfixedly disposed in the internal volume 3213 of the housing 3210, thelead screw 3242 translates linearly along the longitudinal axis A_(L).This urges the puncturing member 3240 to also translate and advancedeeper into the ocular tissue layers. The adjustment member 3230 can berotated until the bearing 3220 approaches a second indent 3235 of theset of the indents 3235. At least a portion of the bearing 3220 movesinto the second indent 3235 and thus prevents further rotation of theadjustment member 3230 by the second torque. Each indent 3235 cancorrespond to predetermined length of the puncturing member 3240protruding through the distal end 3274 of the hub 3270. For example, thesecond indent 3235 can correspond to a protrusion length of thepuncturing member 3240 of about 950 microns. A third indent 3235 cancorrespond to a protrusion length of the puncturing member 3240 of about1050 microns, and so on. Thus, in some embodiments, each indent 3235 cancorrespond to a difference in protrusion length of the puncturing member3240 of about 100 microns. Since, in the second configuration, thebearing 3220 is disposed in the second indent 3235, the adjustmentmember 3230 can no longer be rotated by application of the secondtorque. The user can now apply a third torque, greater than the secondtorque (e.g., substantially equal to the first torque) to further rotatethe adjustment member 3230, thereby increasing the protrusion length orotherwise insertion depth of the puncturing member 3240. In this manner,the needle assembly 3200 can serve as a digital length adjustmentmechanism to allow the user to adjust a protrusion length or otherwiseinsertion depth of the puncturing member 3240 in discrete increments,reliably and repeatably. Furthermore, the different torques required forrotation of the adjustment member 3240 at different positions of thebearing 3220 relative to the indents 3235, also provide a tactilefeedback to the user in adjusting the protruding length or otherwiseinsertion depth of the puncturing member 3240.

In some embodiments, a device includes an adjustment member configuredto move relative to a hub and/or a puncture member. Moreover, althoughbeing described above as transitionable between a first configurationand a second configuration, in some embodiments, an adjustment membercan be transitionable between any number of configurations and/orpositions. For example, FIGS. 34-36 are schematic illustrations of aportion of a delivery device according to an embodiment. As shown inFIG. 34 , a hub 4270 is coupled to a puncture member 4240 and anadjustment member 4230. The hub 4270 has a proximal end portion 4271 anda distal end portion 4272. The proximal end portion 4271 can bephysically and fluidically coupled to a fluid reservoir such as, forexample, the housing 4230 of the delivery device 400, 100, 1000, 2000,3000, or any other delivery device or medical injector describedherein). Although not shown in FIGS. 34-36 , the proximal end portion4271 of the hub 4270 can be coupled to a housing of a delivery deviceusing any suitable coupling method such as, for example, a press fit, asnap fit, a threaded coupling, a Luer connection, a mechanical fastener,an adhesive, and/or the like. In other embodiments, the hub 4270 can bemonolithically formed with a housing of a delivery device. For example,the hub 4270 can be included in and/or form distal end portion of ahousing (e.g., the medical containment chamber 1310, 2310, 3310, or anyother medical containment chamber described herein). Thus, an innervolume of the hub 4270 can be placed in fluid communication with a drugformulation contained within a fluid reservoir (e.g., a medicamentcontainer or the like not shown in FIGS. 34-36 ).

As shown in FIG. 34 , the distal end portion 4272 of the hub 4270includes a substantially elongate portion that includes a set of annularwalls 4274. As described in further detail herein, the annular walls4274 have an outer surface 4275 that includes and/or forms a set ofthreads 4277 that are configured to engage a portion of the adjustmentmember 4230. The annular walls 4274 define a lumen 4276 that extendsthrough the distal end portion 4272 of the hub 4270. The lumen 4276 isconfigured to receive a portion of the puncture member 4240 tophysically and fluidically couple the puncture member 4240 to the hub4270.

The puncture member 4240 (also referred to herein as “microneedle”) canbe configured to puncture and/or penetrate a portion of the eye todeliver a drug formulation to, for example, the suprachoroidal space. Insome embodiments, the puncture member 4240 can be a 32-gauge microneedleor a 34-gauge microneedle. The microneedle 4240 has a proximal endportion 4242 and a distal end portion 4244, and defines a lumen 4241. Asshown in FIG. 34 , the proximal end portion 4242 is disposed within thelumen 4276 of the hub 4270. For example, in some embodiments, the hub4270 can be over-molded about the proximal end portion 4242 of thepuncture member 4240. In other embodiments, the hub 4270 and thepuncture member 4240 can be monolithically formed (e.g., the puncturemember 4240 can be a microcatheter or the like that is unitarily formedwith the hub 4270). Therefore, with the hub 4270 physically andfluidically coupled to a housing or fluid reservoir (as describedabove), the lumen 4241 of the puncture member 4240 can be placed influid communication with a drug formulation contained therein.

As described above, the lumen 4241 of the puncture member 4240 extendsthrough the proximal end portion 4242 and the distal end portion 4244.In this manner, the lumen 4241 can be placed in fluid communication witha volume substantially outside the microneedle 4240. The distal endportion 4244 can be any suitable shape, size, or configuration. Forexample, in some embodiments, the distal end portion 4244 can form abevel or the like. In some embodiments, the distal end portion 4244 canbe substantially similar to or the same as those described in the '009PCT application incorporated by reference above. In this manner, thedistal end portion 4244 of the puncture member 4240 can be configured topierce an ocular tissue while minimizing deformation of the tissue atthe insertion site.

As shown, the microneedle 4240 extends from the distal end portion 4272of the hub 4270 in the distal direction. In this manner, the microneedle4240 can have a shaft length H between a distal edge 4245 of thepuncture member 4240 and a distal surface of the hub 4270. The shaftlength H can be any suitable length. For example, in some embodiments,the shaft length H can substantially correspond to at least a portion ofthe eye. In some embodiments, the shaft length H can be such that whenthe microneedle 4240 is inserted into the eye, the distal end portion4244 of the microneedle 4240 is disposed within the suprachoroidal spacewithout puncturing the choroid. By way of example, the shaft length H ofthe microneedle 4240 can be about 1000 μm or less, about 900 μm or less,about 850 μm or less, about 800 μm or less, about 750 μm or less, about700 μm or less, about 650 μm or less, or about 600 μm or less. In someembodiments, the shaft length H of the microneedle 4240 can be about 750μm. In other embodiments, the shaft length of the microneedle 4240 canbe about 800 μm, or about 850 μm, or about 900 μm, or about 950 or about1 mm.

The adjustment member 4230 can be any suitable shape, size, orconfiguration and can be movably disposed about a portion of the hub4270 and the puncture member 4240. The adjustment member 4230 has aproximal end portion 4231 and a distal end potion 4232 and defines anopening 4236 therethrough. Moreover, the adjustment member 4230 includesan inner surface 4235 includes and/or forms a set of threads 4237 thatcan matingly engage the threads 4277 of the hub 4270 (described above).In this manner, the distal end portion 4272 of the hub 4270 can bemovably disposed within a portion of the opening 4236. For example, withthe distal end portion 4272 of the hub 4270 disposed within the portionof the opening 4236, the adjustment member 4230 can be rotated relativeto the hub 4270 to advance the threads 4237 of the adjustment member4230 along a length of the threads 4277 of the hub 4270. Thus, theadjustment member 4230 can be moved between a first position relative tothe hub 4270 (e.g., a distal position, see e.g., FIGS. 34 and 35 ) and asecond position relative to the hub 4270 (e.g., a proximal position, seee.g., FIG. 36 ). Moreover, the adjustment member 4230 can be moved toany number of different positions relative to the hub 4270.

The arrangement of the hub 4270, the adjustment member 4230 and thepuncture member 4240 is such that a portion of the puncture member 4240is disposed within the opening 4236 defined by the adjustment member4230 while the distal end portion 4244 of the puncture member 4240extends beyond a distal surface 4234 of the adjustment member 4230. Forexample, as shown in FIG. 34 , the distal end portion 4244 of thepuncture member 4240 can extend a distance D₁ (also referred to as aneffective length of the puncture member 310) from the distal surface4234 of the adjustment member 4230. Similarly stated, the distal edge4245 of the puncture member 4240 is spaced apart from the distal surfaceof the adjustment member 4230 by the distance D₁. Thus, when theadjustment member 4230 is moved a given distance relative to the hub4270, the effective length of the puncture member 4240 (i.e., thedistance D₁) is changed by a corresponding distance. By way of example,while the adjustment member 4230 is in the first position relative tothe hub 4270 (e.g., the distal position), the distance D₁ can be, forexample, 350 μm and when the adjustment member 4230 is moved to thesecond position relative to the hub 4270 (e.g., the proximal position),the distance D₁ can be increased to, for example, 650 μm. In otherembodiments, the distance D₁ can be increased to, for example, 500 μm,550 μm, 600 μm, 700 μm, 750 μm, 800 μm, 850 μm, 900 μm, 950 μm, or anysuitable fraction thereof.

As shown in FIGS. 35 and 36 , in use, a user (e.g., a doctor,technician, nurse, physician, ophthalmologist, etc.) can manipulate adelivery device (not shown) to insert the puncture member 4240 into, forexample, a portion of the eye 10. In this manner, the distal end portion4244 of the puncture member 4240 can be advanced through a portion ofthe sclera 20 until the distal surface 4234 of the adjustment member4230 is placed in contact with an outer surface of the sclera 20. Withthe adjustment member 4230 in the first configuration, the distance D₁(e.g., the first distance) between the distal surface 4234 of theadjustment member 4230 and the distal edge 4245 of the puncture member4240 can substantially depend on and/or be associated with the thicknessof the sclera 20. For example, in some embodiments, when the adjustmentmember 4230 is in the first configuration, the distance D₁ (FIG. 34 )between the adjustment member 4230 and the distal edge 4245 can be about450 μm. In other embodiments, the distance D₁ when the adjustment member4230 is in the first configuration can be about 350 μm, 400 μm, 500 μm,550 μm, 600 μm, 650 μm, 700 μm, 750 μm, or any fraction therebetween. Instill other embodiments, the distance D₁ when the adjustment member 4230is in the first configuration can be less than 350 μm. In this manner,the distal edge 4245 of the puncture member 4240 can be disposed withinthe sclera 20, as shown in FIG. 35 . While shown in FIG. 35 as beingdisposed entirely in the sclera 20, in other embodiments, at least aportion of the distal edge 4245 can be disposed within thesuprachoroidal space 36.

The adjustment member 4230 can be moved from its first position relativeto the hub 4270 to its second position relative to the hub 4270 toincrease the distance D₁ (FIG. 34 ) between the adjustment member 4230and the distal edge 4245 of the puncture member 4240 from the firstdistance (FIG. 35 ) to a second distance, as shown in FIG. 36 . Forexample, in some embodiments, a user can manipulate a grip portion(e.g., a textured finish and/or a set of handles, ribs, detents,grooves, etc.) of the adjustment member 4230 to rotate the adjustmentmember 4230 relative to the hub 4270, as indicated by the arrow AA inFIG. 36 . In this manner, the threads 4237 of the adjustment member 4230are advanced along a length of the threads 4277 of the hub 4270. Thus,the hub 4270 is moved in a distal direction relative to the adjustmentmember 4230 such that the adjustment member 4230 is placed its secondposition relative to the hub 4270, as indicated by the arrow BB in FIG.36 . The movement of the adjustment member 4230 can be performed at anysuitable time, i.e., either before or while the puncture member 4240 isdisposed within the sclera 20.

Expanding further, by rotating the adjustment member 4230 relative tothe hub 4270 (as indicated by the arrow AA), the adjustment member 4230is placed in its second position relative to the hub 4270. Thus, withthe adjustment member 4230 in the second position, the distance D₁ (FIG.34 ) is increased between the distal surface 4234 of the adjustmentmember 4230 and the distal edge 4245 of the puncture member 4240 (e.g.,to the second distance). In some embodiments, the distance D₁ can beincreased to about 600 μm. In other embodiments, the distance D₁ can beincreased to about 650 μm, 700 μm, 750 μm, 800 μm, 850 μm, 900 μm, 950μm, 1000 μm, or any fraction therebetween. In still other embodiments,the distance D₁ can be increased to less that 600 μm (e.g., such as, forexample, in use on pediatric eyes).

As shown in FIG. 36 , the distal movement of the hub 4270 can allow thedistal end portion 4244 of the puncture member 4240 (e.g., in a distaldirection) to be moved distally relative to the sclera 20 to place thelumen 4241 of the puncture member 4240 in fluid communication with thesuprachoroidal space 36. With the lumen 4241 of the puncture member 4240in fluid communication with the suprachoroidal space 36, a drugformulation (contained within a fluid reservoir that is in fluidcommunication with the lumen 4241, for example, as described above withreference to the medical injector 400 of FIGS. 19-20 ) can be expelledthrough the lumen 4241 of the puncture member 4240 and into thesuprachoroidal space 36 of the eye 10. In this manner, the drugformulation can flow within the suprachoroidal space 36 to be deliveredto, for example, the posterior region of the eye (e.g., the posteriorregion 14 of the eye 10 in FIG. 1 ). Moreover, with the adjustmentmember 4230 in the second configuration, the distance between the distalsurface 4234 of the adjustment member 4230 and the distal edge 4245 ofthe puncture member 4240 (e.g., the distance D₁ in FIG. 34 ) can be lessthan a combined thickness of the sclera 20 and the suprachoroidal space36 such that the distal end portion 4244 of the puncture member 4240does not pierce the choroid 28.

In some embodiments, the relative position of the distal edge 4245 ofthe puncture member 4240 within the eye can be localized (e.g.,determined, realized, etc.) via any suitable method. For example, insome instances, the amount of force exerted to advance the distal edge4245 of the puncture member 4240 through the sclera 20 can be greaterthan an amount of force exerted to advance the distal edge 4245 throughthe suprachoroidal space 36. Thus, reduction in the amount of force thatis exerted to advance the distal end portion 4244 of the puncture member4240 can indicate to a user the relative position of the distal edge4245 of the puncture member 4240 in the eye. In some instances,imagining techniques (e.g., fluoroscopy, X-ray Computed Tomography (CT)scans, or the like) can be used to provide an indication of the relativeposition of the distal edge 4245 with respect to the anatomy of thetarget tissue.

Although not shown in FIGS. 34-36 , in some embodiments, the hub 4270and/or the adjustment member 4230 can provide an indicator associatedwith the distance D₁ between the adjustment member 4230 and the distaledge 4245 of the puncture member 4240. In some embodiments, theindicator can be a visual indicator such as a measuring scale or thelike. For example, in some embodiments, the puncture member 4240 caninclude indicia (e.g., lines, markings, tic marks, etc.) that representsa gradation of a length of the puncture member 4240 associated with thedistance D₁ between the distal surface 4234 of the adjustment member4230 and the distal edge 4245 of the puncture member 4240. In someembodiments, the markings can represent distances of 100 microns orless. In this manner, a user can view the indicia to determine, forexample, a change in the distance D₁ that would otherwise beindeterminate. In other embodiments, the adjustment member 4230 and/orthe hub 4270 can produce a audible or haptic indicator such as, forexample, a “clicking” sound or the like.

Although the adjustment member 4230 is described above with reference toFIGS. 34-36 as rotating about the hub 4270 to change the distance (e.g.,the distance D₁ in FIG. 34 ) between the distal surface 4234 of theadjustment member 4230 and the distal edge 4245 of the puncture member4240, in other embodiments, an adjustment member can be transitionedrelative to a hub in any suitable manner. For example, in someembodiments, an outer surface of a hub can include a set of protrusionsthat can engage a set of detents defined by an inner surface of anadjustment member (or vice versa). In such embodiments, the adjustmentmember can be moved linearly relative to the hub such that the detentsof the adjustment member sequentially engage the protrusions of the hub.

FIG. 37 is a schematic illustration of a portion of a delivery deviceaccording to an embodiment. As shown, a hub 5270 is coupled to apuncture member 5240 and an adjustment member 5230. The hub 5270 has aproximal end portion 5271 and a distal end portion 5272. The proximalend portion 5271 can be physically and fluidically coupled to a fluidreservoir such as, for example, the medicament container 430 of themedical injector 400 described above with reference to FIGS. 19-20 , orany other medicament container described herein. Although not shown inFIG. 37 , the proximal end portion 5271 of the hub 5270 can be coupledto a housing (e.g., a medicament container) of a delivery device usingany suitable coupling method such as, for example, a press fit, a snapfit, a threaded coupling, a Luer connection, a mechanical fastener, anadhesive, and/or the like. In other embodiments, the hub 5270 can bemonolithically formed with a housing of a delivery device. For example,the hub 5270 can be included in and/or form a distal end portion of ahousing (e.g., distal end portion 434 of the medicament container 430).Thus, an inner volume of the hub 5270 can be placed in fluidcommunication with a drug formulation contained within a fluid reservoir(e.g., a medicament container), as described above with reference to thehub 4270 of FIGS. 34-36 . As shown in FIG. 37 , the distal end portion5272 of the hub 5270 can be a substantially elongate portion thatincludes and/or is formed from a set of annular walls 5274. As describedin further detail herein, the annular walls 5274 define a lumen 5276that extends through the distal end portion 5272 of the hub 5270. Thelumen 5276 is configured to receive a portion of the puncture member5240 to physically and fluidically couple the puncture member 5240 tothe hub 5270.

The puncture member 5240 (also referred to herein as “microneedle”) canbe configured to puncture and/or penetrate a portion of the eye todeliver a drug formulation to, for example, the suprachoroidal space.The microneedle 5240 has a proximal end portion 5242 and a distal endportion 5244, and defines a lumen 5241. As shown in FIG. 37 , theproximal end portion 5242 is disposed within the lumen 5276 of the hub5270. For example, in some embodiments, the hub 5270 can be over-moldedabout the proximal end portion 5242 of the puncture member 5240. Inother embodiments, the hub 5270 and the puncture member 5240 can bemonolithically formed (e.g., the puncture member 5240 can be amicrocatheter or the like that is unitarily formed with the hub 5270).Therefore, with the hub 5270 physically and fluidically coupled to ahousing or fluid reservoir (as described above), the lumen 5241 of thepuncture member 5240 can be placed in fluid communication with a drugformulation contained therein.

As shown, the microneedle 5240 extends from the distal end portion 5272of the hub 5270 in the distal direction. In this manner, the microneedle5240 can have a shaft length H between a distal edge 5245 of thepuncture member 5240 and a distal surface of the hub 5270. In thismanner, the puncture member 5240 can be substantially similar to or thesame as the puncture member 4240 described above with reference to FIGS.34-46 . Thus, portions of the puncture member 5240 are not described infurther detail herein.

The adjustment member 5230 can be any suitable shape, size, orconfiguration and is transitionable between a first configuration and asecond configuration. The adjustment member 5230 is coupled to thedistal end portion 5272 of the hub 5270. For example, in someembodiments, the adjustment member 5230 can be coupled to the hub 5270via a press fit, a snap fit, a threaded coupling, mechanical fastener,an adhesive, and/or the like. In other embodiments, the adjustmentmember 5230 can be disposed about a portion of the puncture member 5240such that a portion of the adjustment member 5230 is in contact with thedistal end portion 5272 of the hub 5270 (e.g., adjacent to yet notcoupled to the hub 5270). In this manner, the hub 5270 and the puncturemember 5240 can be reusable (after sterilization) and can be temporarilycoupled to a disposable adjustment member 5230. In some embodiments, theadjustment member 5230 and the hub 5270 can be monolithically formed. Insome embodiments, the adjustment member 5230 can be over-molded aboutthe distal end portion 5272 of the hub 5270. For example, in someembodiments, the hub 5270 can be formed from a relatively rigid materialsuch as a metal or hard plastic and can act as a substrate about whichthe adjustment member 5230 is molded (e.g., from a relatively softmaterial such as an elastomeric material, thermoplastic, rubber,silicone, or the like). As shown in FIG. 37 , when the adjustment member5230 is in the first configuration, the adjustment member 5230 has athickness T₁. In some embodiments, the thickness T₁ of the adjustmentmember 460 can be, for example, about 25 μm, 50 μm, 100 μm, 400 μm, orany suitable fraction therebetween. In other embodiments, the adjustmentmember 5230 can have a thickness T₁ that is greater than 400 μm. Inother embodiments, the overall thickness T₁ of the adjustment member5230 can be less than about 25 μm.

The adjustment member 5230 is removably disposed about a portion of thepuncture member 5240. More specifically, the puncture member 5240 canextend in the distal direction from the hub 5270 such that a portion ofthe puncture member 5240 extends through the adjustment member 5230. Forexample, as shown in FIG. 37 , the distal end portion 5244 of thepuncture member 5240 can extend a distance (i.e., D₂ or D₃) from adistal surface 5234 of the adjustment member 5230. Similarly stated, thedistal edge 5245 of the puncture member 5240 is spaced apart from thedistal surface 5234 of the adjustment member 5230 by the distance D₂(also referred to as an effective length of the puncture member 5240).As described above, the adjustment member 5240 can be transitionedbetween a first configuration and a second configuration. Morespecifically, the first configuration can be associated with the firstthickness T₁ of the adjustment member 5230 and the second configurationcan be associated with a second thickness T₂. Thus, when the adjustmentmember 5230 is moved from the first configuration to the secondconfiguration (e.g., from the first thickness T₁ to the second thicknessT₂), the effective length of the puncture member 5240 between the distaledge 5245 of the puncture member 5240 and the distal surface 5234 of theadjustment member 5230 is increased by a corresponding distance (e.g.,increased from the first distance D₁ to a second distance D₃). Similarlystated, the nominal change in the thickness from the first thickness T₁to the thickness T₂ substantially corresponds with (or is the same as)the nominal change in distance from the first distance D₂ to the seconddistance D₃. By way of example, while the adjustment member 5230 is inthe first configuration, the first thickness T₁ can be, for example, 250μm and the first distance D₂ can be, for example, about 450 μm. When theadjustment member 5230 is moved to the second configuration, the secondthickness T₂ of the adjustment member 5230 can be, for example, 100 μmand the second distance D₃ can be, for example, about 600 μm.

In use, a user (e.g., a doctor, technician, nurse, physician,ophthalmologist, etc.) can manipulate a delivery device (not shown) toinsert the puncture member 5240 into, for example, a portion of the eye(e.g., the eye 10 shown in FIG. 1 ). In this manner, the distal endportion 5244 of the puncture member 5240 can be advanced through aportion of the sclera until the distal surface 5234 of the adjustmentmember 5230 is placed in contact with an outer surface of the sclera.With the adjustment member 5230 in the first configuration, the distanceD₂ (e.g., the first distance) between the distal surface 5234 of theadjustment member 5230 and the distal edge 5245 of the puncture member5240 can substantially depend on and/or can be associated with thethickness of the sclera. For example, in some embodiments, when theadjustment member 5230 is in the first configuration, the distance D₂between the distal surface 5234 of the adjustment member 5230 and thedistal edge 5245 can be about 550 μm. In other embodiments, the distanceD₂ when the adjustment member 5230 is in the first configuration can beabout 350 μm, 400 μm, 450 μm, 500 μm, 600 μm, 650 μm, 700 μm, 750 μm,800 μm, 850 μm, 900 μm, 950 μm, 1000 μm, or any fraction therebetween.In still other embodiments, the distance D₂ when the adjustment member5230 is in the first configuration can be less than about 350 μm. Inthis manner, a distal edge 5245 of the puncture member 5240 can bedisposed within the sclera (e.g., the sclera 20 of the eye 10 in FIG. 1).

The adjustment member 5230 can be moved from its first configuration toits second configuration to increase the distance between the distalsurface 5234 of the adjustment member 5230 and the distal edge 5245 ofthe puncture member 5240 from the first distance D₂ to the seconddistance D₃. For example, in some instances, a user can exert a force(either directly or indirectly) on the hub 5270 to advance the puncturemember 5240 relative to the eye. With the distal surface 5234 of theadjustment member 5230 in contact with an outer surface of the sclera,the force exerted on the hub 5270 can be operable in compressing theadjustment member 5230 from the first thickness T₁ to the secondthickness T₂. Thus, the adjustment member 5230 is placed in the secondconfiguration and the distance between the distal surface 5234 of theadjustment member 5230 is increased from the first distance D₂ to thesecond distance D₃. For example, in some instances, the second distanceD₃ can be about 600 μm. In other embodiments, the second distance D₃ canbe about 650 μm, 700 μm, 750 μm, 800 μm, 850 μm, 900 μm, 950 μm, 1000μm, or any fraction therebetween. In still other embodiments, the seconddistance D₃ can be increased to less than about 600 μm (e.g., such as,for example, in use on pediatric eyes).

As described above with reference to FIG. 36 , the movement of theadjustment member 5230 to the second configuration can be such thatfurther movement of the puncture member 5240 (e.g., in a distaldirection) relative to the sclera places the lumen 5241 of the puncturemember 5240 in fluid communication with the suprachoroidal space (e.g.,the suprachoroidal space 36 of the eye 10 in FIG. 1 ). Similarly stated,the increase in distance from the first distance D₂ to the seconddistance D₃ can be sufficiently large to extend the distal edge 5245 ofthe puncture member 5240 through the sclera such that the lumen 5241 isplaced in fluid communication with the suprachoroidal space. With thelumen 5241 of the puncture member 5240 in fluid communication with thesuprachoroidal space, a drug formulation (contained within a fluidreservoir as described above with reference to FIG. 36 ) can be expelledthrough the lumen 5241 of the puncture member 5240 and into thesuprachoroidal space of the eye. In this manner, the drug formulationcan flow within the suprachoroidal space to be delivered to, forexample, the posterior region of the eye (e.g., the posterior region 14of the eye 10 in FIG. 1 ). Moreover, with the adjustment member 5230 inthe second configuration, the distance between the distal surface 5234of the adjustment member 5230 and the distal edge 5245 of the puncturemember 5230 (e.g., the second distance D₃) can be less than a combinedthickness of the sclera and the suprachoroidal space such that thedistal end portion 5244 of the puncture member 5240 does not pierce thechoroid.

In addition to adjusting and/or controlling the effective length of thepuncture member 5240 to enhance the likelihood that the lumen 5241 isplaced in fluid communication with the desired region of the targettissue (e.g., the suprachoroidal space of the eye), in some embodiments,the adjustment member 5230 (and any of the adjustment members shown anddescribed herein) can form a substantially fluid-tight seal and/or asubstantially liquid-tight seal with the outer surface of the targettissue (e.g., the conjunctiva of the eye). In this manner, leakage ofthe injected medicament along the needle track during the injectionevent can be reduced and/or eliminated. Expanding further, in someembodiments, the anatomy of the target tissue and/or the arrangement ofthe delivery device can be such that, in use, a portion of the openingof the lumen 5241 may be placed in fluid communication with thesuprachoroidal space 36 of the eye, while another portion of the openingof the lumen 5241 may be positioned within the sclera 20. Thus, when thedrug formulation is conveyed into the eye via the puncture member 5240,a portion of the drug formulation may be prone to migrating away fromthe desired region (e.g., the suprachoroidal space 36) and out of theeye via the needle track. By forming a substantially fluid-tight sealand/or a substantially liquid-tight seal, the adjustment member 5230 canproduce an area of high resistance to flow, thus minimizing and/oreliminating the flow migration and/or leakage.

Although the adjustment member 5230 is described above as beingconstructed from a relatively soft material, which can be well suited toforming a fluid-tight seal, in some embodiments, the adjustment member5230 can be constructed from multiple materials. For example, in someembodiments, the distal end surface 5234 of the adjustment member 5230can be constructed from and/or can include a layer or portionconstructed from a material formulated to form a substantiallyfluid-tight seal with the outer surface of the target tissue (e.g., theconjunctiva).

Although not shown in FIG. 37 , in some embodiments, the adjustmentmember 5230 and/or the puncture member 5240 can include a lockingfeature that can be configured to at least temporarily retain theadjustment member 5230 in the second configuration. For example, in someembodiments, the puncture member 5240 and/or hub 5270 can include one ormore detents, grooves, protrusions, etc. that can matingly engage aportion of the adjustment member 5230 to retain the adjustment member5230 in the second configuration. More specifically, in someembodiments, the adjustment member 5230 can include a set of protrusions(not shown) that extend from the adjustment member toward the puncturemember 5240. In such embodiments, the adjustment member 5230 can bemoved to the second configuration to decrease the thickness of theadjustment member (as described above). In this manner, the protrusionscan move along a surface of the puncture member 5240 while theadjustment member 5230 is being moved to the second configuration. Oncethe adjustment member 5230 is in the second configuration, theprotrusions can matingly engage a set of detents that can at leasttemporarily retain the protrusions therein. Thus, the adjustment member5230 can be at least temporarily locked in the second configuration. Inother embodiments, the adjustment member 5230 and the puncture member5240 do not include a locking feature and a user can exert asubstantially constant force to retain the adjustment member 5230 in thesecond configuration.

In some embodiments, the puncture member 5240 and/or the adjustmentmember 5230 can include a visual indicator that is associated with thedistance between the distal surface 5234 of the adjustment member 5230and the distal edge 5245 of the puncture member 5240. For example, insome embodiments, the puncture member 5240 can include a measurementindicator. In such embodiments, a user determine the distance betweenthe distal surface 5234 of the adjustment member 5230 and the distaledge 5245 of the puncture member 5240 by visually inspecting themeasurement indicator.

FIG. 38 is a schematic illustration of a portion of a delivery deviceaccording to an embodiment. As shown, a hub 6270 is coupled to apuncture member 6240 and an adjustment member 6230. The hub 6270 has aproximal end portion 6271 and a distal end portion 6272. The proximalend portion 6271 can be physically and fluidically coupled to a fluidreservoir such as, for example, the medicament container 430 of themedical injector 400 described above with reference to FIGS. 19-20 .Although not shown in FIG. 38 , the proximal end portion 6271 of the hub6270 can be coupled to a housing (e.g., a medicament container) of adelivery device using any suitable coupling method such as, for example,a press fit, a snap fit, a threaded coupling, a Luer connection, amechanical fastener, an adhesive, and/or the like. In other embodiments,the hub 6270 can be monolithically formed with a housing of a deliverydevice. For example, the hub 6270 can be included in and/or form adistal end portion of a housing (e.g., the distal end portion 343 of thehousing 430). Thus, an inner volume of the hub 6270 can be placed influid communication with a drug formulation contained within a fluidreservoir (e.g., a housing), as described above with reference to thehub 6270 of FIGS. 34-36 . As shown in FIG. 38 , the distal end portion6272 of the hub 6270 can be a substantially elongate portion thatincludes and/or is formed from a set of annular walls 6274. The annularwalls 6274 define a lumen 6276 that extends through the distal endportion 6272 of the hub 6270. The lumen 6276 is configured to receive aportion of the puncture member 6270 to physically and fluidically couplethe puncture member 6270 to the hub 6270.

The puncture member 6240 (also referred to herein as “microneedle”) canbe configured to puncture and/or penetrate a portion of the eye todeliver a drug formulation to, for example, the suprachoroidal space.The microneedle 6240 has a proximal end portion 6242 and a distal endportion 6244, and defines a lumen 6241. As described above, the proximalend portion 6242 is disposed within the lumen 6276 of the hub 6270. Forexample, in some embodiments, the hub 6270 can be over-molded about theproximal end portion 6242 of the puncture member 6240. In otherembodiments, the hub 6270 and the puncture member 6240 can bemonolithically formed (e.g., the puncture member 6240 can be amicrocatheter or the like that is unitarily formed with the hub 6270).Therefore, when the hub 6270 is physically and fluidically coupled to ahousing or fluid reservoir (as described above), the lumen 6241 of thepuncture member 6240 can be placed in fluid communication with a drugformulation contained therein.

As shown, the microneedle 6240 extends from the distal end portion 6272of the hub 6270 in the distal direction. The microneedle 6240 has ashaft length H between a distal edge 6245 of the puncture member 6240and a distal surface of the hub 6270. In this manner, the puncturemember 6240 can be substantially similar to or the same as the puncturemember 6240 described above with reference to FIGS. 34-36 . Thus,portions of the puncture member 6240 are not described in further detailherein.

The adjustment member 6230 can be any suitable shape, size, orconfiguration and can be disposed about a portion of the hub 6270 and/orthe puncture member 6240. For example, although some of the adjustmentmembers are described herein as being monolithic, in other embodiments,such as here, an adjustment member can be constructed from multipledifferent components that are joined together. In particular, theadjustment member 6230 includes a base 6238 and a set of removablelayers 6239. The base 6238 is coupled to the distal end portion 6272 ofthe hub 6270. For example, in some embodiments, the base 6238 can beremovably coupled to the hub 6270 (e.g., via a press fit, a snap fit, athreaded coupling, mechanical fastener, and/or the like). In thismanner, the hub 6270 can be reusable (after sterilization) and can betemporarily coupled to a disposable adjustment member 6230. In otherembodiments, the base 6238 can be fixedly coupled to the hub 6270 (e.g.,via an adhesive, ultrasonic welding, and/or the like).

The set of layers 6239 is comprised of relatively thin strips that aresequentially stacked on one another. More specifically, a first layer6239 is removably coupled to the base 6238 and each subsequent layer6239 is stacked on top of the preceding layer. In some embodiments, thelayers 6239 can be relatively thin strips of a self-adhering flexiblematerial such as sheets of polyethylene, polyvinylidene chloride,polypropylene, polyacrylate, or the like. In other embodiments, thelayers 6239 can be at least temporarily retained to each other and/or tothe hub via an adhesive. In such embodiments, the layers 6239 can beretained by one or more adhesive material having varying adhesivestrengths. For example, in some embodiments, the adhesive strengthbetween adjacent layers 6239 can increase from a first adhesive strengthbetween the distal-most layer and its adjacent layer and a secondadhesive strength between the proximal-most layer and its adjacentlayer. In some embodiments, each layer can be adhered to an adjacentlayer by a unique adhesive. In other embodiments, each layer can beadhered to an adjacent layer by the same adhesive with, for example,varying adhesive strengths. In yet other embodiments, the layers can beretained via a combination of an adhesive and one or more self-adhesivematerial. In this manner, one or more layers 6239 can be removed fromthe set of layers 6239 to transition the adjustment member 6230 from thefirst configuration to the second configuration. Moreover, by varyingthe properties of the adhesive, the user can more easily remove thedesired layer(s) without inadvertently removing additional layers.

As shown in FIG. 38 , each layer 6239 has a thickness TL. In someembodiments, the thickness TL of each layer 6239 can be, for example,about 5 μm, 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 100 μm, or any suitablefraction therebetween. In other embodiments, a layer 6239 can have athickness TL that is greater than 100 Although each layer 6239 is shownand described as having substantially the same thickness TL, in otherembodiments, the layers 6239 can have varying thickness. As shown inFIG. 38 , the set of layers 6239 can have an overall thickness TA thatis the sum of the thicknesses TL of each stacked layer 6239. Forexample, in some embodiments, the overall thickness TA of the set oflayers 6239 can be about 50 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm,400 μm, 500 μm, 1000 μm, or any suitable fraction therebetween. In otherembodiments, the overall thickness TA of the set of layers 6239 can beless than about 50 μm. In still other embodiments, the overall thicknessTA of the set of layers 6239 can be greater than about 1000 μm. Althoughthree removable layers 6239 are shown in FIG. 38 , in other embodiments,an adjustment member can include any suitable number of removable layers(e.g., two layers, four layers, five layers, six layers, seven layers,eight layers, nine layers ten layers, or more).

As described above, the adjustment member 6230 is disposed about aportion of the hub 6270 and the puncture member 6270. More specifically,the puncture member 6240 can extend in the distal direction from the hub6240 such that a portion of the puncture member 6240 extends through theadjustment member 6230 (e.g., through the base 6238 and the set oflayers 6239). For example, as shown in FIG. 38 , the distal end portion6244 of the puncture member 6240 can extend a distance D₄ from theoutermost layer 6239 of the adjustment member 6230 (also referred to asan effective length of the puncture member 6240). Similarly stated, thedistal edge 6245 of the puncture member 6240 is spaced apart from adistal surface of the adjustment member 6230 (e.g., the outermost layer6239) by the distance D₄. Thus, when a layer 6239 is removed from theset of layers 6239 of the adjustment member 6230, the effective lengthof the puncture member 6240 (e.g., the distance D₄) is increased by adistance that substantially corresponds to the thickness TL of the layer6239 that was removed. By way of example, while the adjustment member6230 is in the first configuration (e.g., where all the layers includedin the set of layers 6239 are stacked), the distance D₄ can be, forexample, about 550 μm and when the adjustment member 6230 is moved tothe second configuration (e.g., when one or more layers are removed fromthe set of layers 6239), the distance D₄ can be increased to, forexample, about 650 μm. In other embodiments, the effective length of thepuncture member 6240 can be increased to 600 μm, 700 μm, 750 μm, 800 μm,850 μm, 900 μm, 950 μm, 1000 μm, or any suitable fraction therebetween.

In use, a user (e.g., a doctor, technician, nurse, physician,ophthalmologist, etc.) can manipulate a delivery device (not shown) toinsert the puncture member 6240 into, for example, a portion of the eye(e.g., the eye 10 shown in FIG. 1 ). In this manner, the distal endportion 6244 of the puncture member 6240 can be advanced through aportion of the sclera until an outermost layer of the set of layers 6239included in the adjustment member 6230 is placed in contact with anouter surface of the sclera. With the adjustment member 6230 in thefirst configuration, the distance D₄ (e.g., a first distance) betweenthe outermost layer 6239 of the adjustment member 6230 and the distaledge 6245 of the puncture member 6240 can substantially depend on and/orcan be associated with the thickness of the sclera. For example, in someembodiments, when the adjustment member 6230 is in the firstconfiguration, the distance D₄ between the outermost layer 6239 of theadjustment member 6230 and the distal edge 6245 can be about 450 μm. Inother embodiments, the distance D₄ when the adjustment member 6230 is inthe first configuration can be about 350 μm, 400 μm, 500 μm, 550 μm, 600μm, 650 μm, 700 μm, 750 μm, or any fraction therebetween. In still otherembodiments, the distance D₄ when the adjustment member 6230 is in thefirst configuration can be less than about 350 μm. In yet otherembodiments, the distance D₄ when the adjustment member 6230 is in thefirst configuration can be greater than 750 In this manner, a distaledge 6245 of the puncture member 6240 can be disposed within the sclera(e.g., the sclera 20 of the eye 10 in FIG. 1 ).

The adjustment member 6230 can be moved from its first configuration toits second configuration to increase the distance D₄ between theoutermost layer 6239 of the adjustment member 6230 and the distal edge6245 of the puncture member 6240 from the first distance to a seconddistance. For example, in some embodiments, a user can manipulate anengagement portion 6280 of one or more layers to remove (e.g., peel,tear, shear, break away, etc.) the one or more layers from the stack oflayers 6239 (i.e., the set of layers). In this manner, the overallthickness TA of the set of layers 6239 is reduced by the combinedthicknesses TL of each layer that is removed. Expanding further, byremoving the one or more layers, the overall thickness TA of the set oflayers 6239 is reduced, thereby placing the adjustment member in thesecond configuration. Thus, with the adjustment member 6230 in thesecond configuration, the distance D₄ is increased between the currentoutermost layer (e.g., the outermost layer after removing the one ormore layers) and the distal edge 6245 of the puncture member 6240 (e.g.,to a second distance). In some embodiments, the distance D₄ can beincreased to about 600 μm. In other embodiments, the distance D₄ can beincreased to about 650 μm, 700 μm, 750 μm, 800 μm, 850 μm, 900 μm, 950μm, 1000 μm, or any fraction therebetween. In still other embodiments,the distance D₄ can be increased to less than about 600 μm (e.g., suchas, for example, in use on pediatric eyes). By way of example, in someembodiments, the adjustment member 6230 can include a set of 10 layers6239 with each layer having a thickness of about 50 μm. In suchembodiments, the distance D₄ between the outermost layer 6239 and thedistal edge 6245 can be, for example, about 450 μm. In some instances,three layers can be removed from the set of 10 layers 6239 to increasethe distance D₄ to about 600 μm.

In addition to adjusting and/or controlling the effective length of thepuncture member 6240 (e.g., by manipulating a layer from the stack oflayers 6239) to enhance the likelihood that the lumen 6241 is placed influid communication with the desired region of the target tissue (e.g.,the suprachoroidal space of the eye), in some embodiments, theadjustment member 6230 (and any of the adjustment members shown anddescribed herein) can form a substantially fluid-tight seal and/or asubstantially liquid-tight seal with the outer surface of the targettissue (e.g., the conjunctiva of the eye). In this manner, leakage ofthe injected medicament along the needle track during the injectionevent can be reduced and/or eliminated. Expanding further, in someembodiments, the anatomy of the target tissue and/or the arrangement ofthe delivery device can be such that, in use, a portion of the openingof the lumen 6241 may be placed in fluid communication with thesuprachoroidal space 36 of the eye, while another portion of the openingof the lumen 6241 may be positioned within the sclera 20. Thus, when thedrug formulation is conveyed into the eye via the puncture member 6240,a portion of the drug formulation may be prone to migrating away fromthe desired region (e.g., the suprachoroidal space 36) and out of theeye via the needle track. By forming a substantially fluid-tight sealand/or a substantially liquid-tight seal, the adjustment member 6230 canproduce an area of high resistance to flow, thus minimizing and/oreliminating the flow migration and/or leakage.

Although the adjustment member 6230 is described above as beingconstructed from a relatively soft material, which can be well suited toforming a fluid-tight seal, in some embodiments, the adjustment member6230 can be constructed from multiple materials. For example, in someembodiments, the adjustment member 6230 can include a set of layers 6239with a first layer constructed from and/or including a portionconstructed from a first material, and a second layer constructed fromand/or including a portion constructed from a second material differentfrom the first material. Further to this example, at least a portion ofthe first material and/or at least a portion of the second material canbe constructed from and/or can include a layer or portion constructedfrom a material formulated to form a substantially fluid-tight seal withthe outer surface of the target tissue (e.g., the conjunctiva).

Although not shown in FIG. 38 , in some embodiments, the layers 6239 canprovide and/or include an indicator associated with the distance D₄between the outermost layer 6269 and the distal edge 6245 of thepuncture member 6230. In some embodiments, the indicator can be indiciasuch as, for example, a value associated with the distance D₄ (e.g., 500μm). In other embodiments, the layers 6239 can be color coded with eachlayer having a different color and each color being associated with aneffective length of the puncture member 6240.

Although not shown in FIG. 38 , in some embodiments, at least a portionof the layers 6239 can be disposed, at least temporarily, within ahousing or the like. For example, in some embodiments, the layers 6239can be coupled to the base 6238, as described above, and a housing canbe disposed about at least a portion of the layers 6239 and the base6238. Expanding further, in some embodiments, the housing can be movablydisposed about the base and can define a window through which theengagement portion 6280 of the layers 6239 can extend. Thus, a user canmanipulate the engagement portion 6280 of a layer 6239 to remove thelayer 6239 from the adjustment member 6230. In some embodiments, thelayer 6239 can be withdrawn through the window defined by the housing.In this manner, the housing can be moved in the proximal direction to beplaced in contact with the outermost layer 6239, thereby allowing ashaft length of the puncture member 6240 between the distal edge 6245and a distal surface of the housing to be increased. In someembodiments, the window can provide for visualization of the shaftlength indicator (described above).

As described above with reference to FIG. 36 , the increase in thedistance D₄ can be such that further movement of the puncture member6240 (e.g., in a distal direction) relative to the sclera places thelumen 6241 of the puncture member 6240 in fluid communication with thesuprachoroidal space (e.g., the suprachoroidal space 36 of the eye 10 inFIG. 1 ). Similarly stated, the increase in the distance D₄ can besufficiently large to extend the distal edge 6245 of the puncture member6240 through the sclera such that the lumen 6241 is placed in fluidcommunication with the suprachoroidal space. Expanding further, byremoving the one or more layers from the set of layers 6239 of theadjustment member 6230, the distance between the outermost layer 6239 ofthe adjustment member 6230 and the distal edge 6245 of the puncturemember 6240 (e.g., the distance D₄) is increased and the user can movethe hub 6270 (e.g., either directly or indirectly) place the currentoutermost layer in contact with the outer surface of the sclera.

With the lumen 6241 of the puncture member 6240 in fluid communicationwith the suprachoroidal space, a drug formulation (contained within afluid reservoir as described above with reference to FIG. 36 ) can beexpelled through the lumen 6241 of the puncture member 6240 and into thesuprachoroidal space of the eye. In this manner, the drug formulationcan flow within the suprachoroidal space to be delivered to, forexample, the posterior region of the eye (e.g., the posterior region 14of the eye 10 in FIG. 1 ). Moreover, with the adjustment member 6230 inthe second configuration, the distance D₄ can be less than a thicknessof the sclera and the suprachoroidal space such that the distal endportion 6244 of the puncture member 6240 does not pierce the choroid.

As described herein, a system, for example, the system 1000, 2000, 3000,or any other system described herein, can include a hub, for example,the hub 3270, 4270, 5270, or any other hub described herein. The hub canbe configured to form a substantially fluid-tight zone around theinsertion site of a puncturing member (e.g., the puncturing member 3240or any other puncturing member described herein) into the eye. Forexample, in some embodiments, a system can include a hub or contactsurface configured to contact a surface of a target tissue to producethe desired effects during medicament delivery (e.g., maintaining aposition of the conjunctiva, forming a seal or the like).

FIG. 39 shows an apparatus 7000 that includes a medical injector 7310,an actuation rod 7320, a needle 7240, and a hub 7270, and optionally aneedle adjustment mechanism 7230. The system 7000 can be configured todeliver a medicament to a target layer of an eye of patient, forexample, to the SCS of the eye.

The medical injector 7310 defines an internal volume 7316 configured tohouse a medicament L (e.g., a VEGF, a VEGF inhibitor, triamcinoloneacetonide, any other medicament described herein or a combinationthereof). The medical injector 7310 includes an engagement portion 7312and a delivery portion 7314 coupled to the needle adjustment mechanism7230. The medical injector 7310 can be substantially similar to themedicament containment chamber 1310, 2310, 3310, or any other medicamentcontainment chamber described herein, and is therefore not described infurther detail herein.

The actuation rod 7320 includes an engagement portion 7322 and a plungerportion 7324. The plunger portion 7324 is slidably disposed inside theinternal volume 7316 defined by the medical injector 7310. Theengagement portion 7322 is configured to be engaged by the user and urgethe plunger portion 7324 to slide within the internal volume 7316defined by the medical injector 7310. For example, the user can apply aforce in the direction shown by the arrow F₁ on the engagement portion7322 to move the plunger portion 7324 proximally relative to the medicalinjector 7310 thereby, expelling at least a portion of the medicament Lthrough a lumen 7241 of the needle 7240. As shown, at least a portion ofthe actuation rod 7320 can be disposed around and concentric with themedical injector 7310. The plunger portion 7324 is configured to draw inthe medicament L into or expel the medicament L from the internal volume7316 defined by the medical injector 7310. In some embodiments, anyother actuation rod can be included in the apparatus 7000, for examplethe actuator 1320, 2320, 3320 or any other actuator described herein.

The needle 7240 defines the lumen 7241 and is configured to pierce theeye and deliver the medicament L into a target tissue of the eye. Theneedle 7240 can be substantially similar to any of the puncturingmembers described herein, and is therefore not described in furtherdetail herein. In some embodiments, the needle 7240 can be a microneedlemovably disposed within a passageway 7276 of the hub 7270, as describedherein. The needle adjustment mechanism 7230 can be coupled to thedelivery portion 7314 of the medical injector 7310 and a proximal end ofthe needle 7240. In some embodiments, the needle adjustment mechanism7230 is configured to move the needle 7240 within the passageway 7276such that a distal end portion of the needle 7240 extends from thedistal end surface 7275 of the hub 7270 by a predetermined amount. Forexample, the needle adjustment mechanism 7230 can urge the needle 7240to translate linearly along the longitudinal axis A_(L) and therebyadjust a length of the needle 7240 protruding through a distal end 7274of the hub 6270. The needle adjustment mechanism 7230 can besubstantially similar to the adjustment member 422, 3200, 4230, 5230,6230, or any other adjustment mechanism or adjustment member describedherein.

The hub 7270 is configured to be coupled to the medical injector 7230.The hub 7270 includes a proximal end 7272 and a distal end 7274. Theproximal end 7272 is coupled to a distal end portion of the needleadjustment mechanism 7230. In some embodiments, the proximal end 7272can be coupled to a housing (not shown) which can be included in thesystem 7000. The hub 7270 defines the passageway 7276 configured toreceive at least a portion of the needle 7240 therethrough. In thismanner, the needle 7240 is configured to pass through the lumen 7276 andinto the eye. The distal end surface 7275 of the hub 7270 is configuredto contact a target tissue (e.g., the conjunctiva of the eye) when themedicament L (or any other substance disposed within the medicalinjector 7230) is conveyed through the needle 7240 into the targettissue. In some embodiments, the distal end surface 7275 of the hub 7270is configured to deform the target surface (e.g., the conjunctiva of theeye) when the distal end surface 7275 is contact with the targetsurface. At least a portion of the distal end surface 7275 can have asubstantially convex shape, for example, a hemispherical shape such thatat least a portion of distal end surface 7275 defines a sealing portion7277. The sealing portion 7277 can be configured to define asubstantially fluid-tight seal with the target surface when the distalend surface 7275 is in contact with the target surface. For example, thedistal end surface 7275 can deform the target surface such that thesealing portion 7277 is contiguous with the target surface and forms thesubstantially fluid-tight seal. In some embodiments, the sealing portion7277 can be symmetric about a center A_(L) of the apparatus 7000 andhence the passageway. This can, for example, facilitate perpendicularapproach of the needle 7240 into the target tissue (e.g., oculartissue). Thus, the size of the insertion zone can be minimized reducingdamage. Furthermore, the needle 7240 can use the shortest path to reacha target region of the target tissue (e.g., the SCS of the eye). Whileshown as being a cross-section, the hub 7270 can be substantiallycylindrical, for example, have a circular cross-section and such thatthe convex shape of the distal end surface 7275 resembles, for example,a hemisphere. In such embodiments, the sealing portion 7277 cancircumferentially surround the needle 7240 to form a hemisphericalsubstantially fluid-tight seal with the target surface. In someembodiments, only a small portion of the sealing portion 7277surrounding the needle 7240 needs to contact and form the substantiallyfluid-tight seal with the target surface. For example, in someembodiments, only a small band of the sealing portion 7277 surroundingthe needle 7240 can contact and form the substantially fluid-tight sealwith the target surface.

In some embodiments, the target tissue is an eye and the target surfaceis a conjunctiva of the eye. For example, FIGS. 40A-C shows a portion ofan eye which includes a conjunctiva C, the sclera S, the suprachoroidalspace SCS (which can be the target layer), and a retina R. As shown inFIG. 40A, in a first configuration, the distal end 7274 of the hub 7270is in contact with a conjunctiva C of an eye and a distal end of theneedle 7240 is disposed in a sclera S of the eye. Further to thisexample, the curved shape of the distal end surface 7275 of the hub 7270can allow for a desired distribution of force(s) to be applied to aportion of the eye, for example, the conjunctiva C. In some embodiments,the curved distal end surface 7275 of the hub 7270 can create a tautspherical injection site. For example, the hub 7274 can deform theconjunctiva C in a radial direction from the center point (i.e., awayfrom where the needle 7240 penetrates) when the system 7000 moves fromthe first configuration to a second configuration (e.g., the secondconfiguration shown in FIG. 40B). In this manner, the conjunctiva C canbe moved into and/or held in a preferable position during the injection.In some instances, this can reduce the puncturing forces to penetratethe surface of the eye. In some embodiments, the “stretching” of theconjunctiva C can minimize and/or eliminate any “bunching” of theconjunctiva C that may otherwise occur, and instead can produce asurface layer (e.g., conjunctiva) having a substantially constantthickness. In some instances, the hub 7270 can, at least temporarily,adhere to a portion of the conjunctiva C. In this manner, the hub 7270can cause movement of and/or stabilize at least a portion of theconjunctiva C such that at least the portion of the conjunctiva C is ina preferable position during the injection.

In some embodiments, the inserting of the needle 7240 into the targettissue (i.e., the conjunctiva and the sclera) can be performed such thata centerline of the delivery passageway and a surface line tangent tothe target surface define an angle of entry of between about 75 degreesand about 105 degrees. For example, as shown in FIG. 40D, a centerlineCL of the lumen 7241 of the needle 7240 can define an insertion angle θwith a surface line tangent ST formed relative to the surface of theconjunctiva C. The insertion angle θ can be in the range of betweenabout 75 degrees and about 105 degrees, inclusive of all rangestherebetween. For example, in some embodiments, the insertion angle θcan be about 90 degrees. Said another way, the needle 7240 can beinserted into the target tissue (i.e., the conjunctiva C, and the scleraS) such that the centerline CL defined by the lumen 7241 of the needle7240 is substantially perpendicular or otherwise normal to the surfaceof the target tissue. In this manner, the size of the insertion zone canbe reduced thereby minimizing injury and inflammation, which can becaused by any lateral travel of the needle 7240 within the targettissue. Furthermore, normal insertion can also provide the shortest pathfor the distal tip of the needle 7240 to reach the target tissue (e.g.,the SCS) thereby, reducing the time required to reach the target tissue(e.g., the SCS).

Referring back to FIGS. 40A-C, to initiate delivery of the medicament Lthe user can apply a force F₂ on the system 7000, for example, on theengagement portion 7322 of the actuation rod 7320. The force F₂ can urgethe plunger portion 7324 to slide within the internal volume 7316 of themedical injector 7310 proximally relative to the medical injector 7310and urge the system into a second configuration. While not shown, insome embodiments, the system 7000 can include an injection assembly, forexample, the injection assembly 100, 2100 or any other injectionassembly described herein configured to exert the force on the actuationrod 7320. In the second configuration, the hub 7270 is pressed againstthe conjunctiva C, such that the conjunctiva C compresses and conformsaround the convex shape of the distal end surface 7275 of the hub 7270.This also pushes the needle 7240 further into the sclera S. Furthermore,at least a portion of the sealing portion 7277 defined by the distal endsurface 7275 is contiguous with the deformed surface of the conjunctivaC such that the sealing portion 7277 defines a substantially fluid-tightseal with the conjunctiva C around the insertion site. In someembodiments, the sealing portion 7277 can be substantially symmetricalabout the centerline CL of the needle 7240 (e.g., as shown in FIG. 40D).In some embodiments, only a circular band of the sealing portion 7277can contact and form a substantially fluid-tight seal with theconjunctiva C surrounding the needle 7240. However, in the secondconfiguration, the distal end of the needle 7240 can still be proximalrelative to but not within the suprachoroidal space SCS, which can bethe target layer for delivery of the medicament L.

In some embodiments, the hub 7270 can be a rigid member that has astiffness substantially greater than the stiffness of the conjunctiva C(e.g., a stiffness substantially similar to a stiffness of stainlesssteel). In such embodiments, application of the force F₂ only deformsthe conjunctiva C, without causing any substantial deformation of thehub 7270. In some embodiments, the hub 7270 can have a stiffness that isintermediate to the stiffness of the conjunctiva C and the sclera S. Insuch embodiments, application of the force F₂ can urge the hub 7270 todeform the conjunctiva C (FIGS. 40B and 40C) until the distal endsurface 7275 of the hub 7270 is proximate to the sclera S. Since thestiffness of the hub 7270 is less than the stiffness of the sclera S,further application of the force F₂ will urge the distal end surface7275 of the hub 7270 to deform without any substantial deformation ofthe sclera S. In this manner, the hub 7270 can prevent application of anexcessive force from causing damage to or otherwise deformation and/orpiercing of the internal layers of the eye.

In a third configuration shown in FIG. 40C, the user can then maintainthe force F₂ and increase the length of the needle 7240 protruding intothe eye, for example, using the needle adjustment mechanism 7230. Thelength of the needle 7240 can be increased until a distal tip or outletof the needle 7240 is within or otherwise near the suprachoroidal spaceSCS. The force F₂ can further depress the distal end surface 7275 of thehub 7270 into the conjunctiva C. This can urge substantially all of thesealing portion 7277 of the distal end surface 7275 to be contiguouswith the conjunctiva C further strengthening the substantiallyfluid-tight seal. In this manner, leakage of the injected medicament Lalong the needle 7240 track during the injection event can be reducedand/or eliminated. Expanding further, in some embodiments, the anatomyof the target tissue and/or the arrangement of the system 7000 can besuch that, in use, a portion of the opening of the lumen 7241 of theneedle 7240 may be placed in fluid communication with the suprachoroidalspace SCS of the eye, while another portion of the opening of the lumen7241 may be positioned within the sclera S. Thus, when the medicament Lis conveyed into the eye via the needle 7240, a portion of themedicament L may be prone to migrating away from the desired region,i.e., the suprachoroidal space SCS and out of the eye via the needle7240 track. By forming a substantially fluid-tight seal and/or asubstantially liquid-tight seal, the hub 7270 can produce an area ofhigh resistance to flow, thus minimizing and/or eliminating the flowmigration and/or leakage.

While not shown, in some embodiments, the system 7000 can include aninjection assembly, for example, the injection assembly 100, 2100 or anyother injection assembly described herein. As described before herein,the injection assembly can be configured to exert a force on themedicament L disposed in the internal volume 7316 of the medicamentcontainment chamber 7310. The force can be sufficient to overcome abackpressure of the suprachoroidal space SCS exerted upon the needleopening, but not the backpressure of the sclera S. In such embodiments,the user can insert the needle 7240 into the sclera S as shown in FIG.40A and activate the injection assembly. The injection assembly canpressurize the medicament L but the backpressure of the sclera S canprevent the medicament L from delivery into the sclera S. As shown inFIG. 40B, the user can continue the insertion of the needle 7240, forexample, by maintaining or increasing a magnitude of the force F₂. Thiscan urge the hub 7240 to deform the conjunctiva C and initiate theformation of the fluid tight seal around the insertion site, asdescribed herein. The force F₂ can be maintained until a distal end ofthe needle 7240 is within or near the suprachoroidal space SCS. Theforce exerted by the injection assembly on the medicament L can nowovercome the backpressure of the suprachoroidal space SCS thereby,initiating communication of the medicament L into or near thesuprachoroidal space SCS as shown in FIG. 40C. In this manner, theinjection assembly can assist the user in determining the location ofthe distal end of the needle 7240 such that the medicament L isdelivered substantially only to the target layer (i.e., thesuprachoroidal space SCS). Furthermore, over excursion of the puncturingmember 7240 beyond the suprachoroidal space SCS (i.e., into the retinaR) can be prevented.

In some embodiments, the needle adjustment mechanism 7230 can be used toensure delivery to the target layer. In such embodiments, the user caninsert the needle 7240 into the sclera S as shown in FIG. 40A andactivate the injection assembly to pressurize the medicament L asdescribed herein. While maintaining the force F₂, the user can use theneedle adjustment mechanism 7230 to advance the needle 7240 inpredetermined increments (e.g., about 100 μm increments) into the scleraS, for example, as described herein with reference to the needleassembly 422, 3200, or any other needle assembly describe herein. Inthis manner, the needle adjustment mechanism 7230 can be used to advancethe needle 7240 through the sclera S until a distal end of the needle7240 is within or near the suprachoroidal space SCS. The force exertedby the injection assembly on the medicament L can now overcome thebackpressure of the suprachoroidal space SCS thereby, initiatingcommunication of the medicament L into or near the suprachoroidal spaceSCS as shown in FIG. 40C. Thus, by allowing the user to advance theneedle 7240 in known discrete increments, the needle adjustmentmechanism 7230 can assist the user in preventing over excursion of theneedle 7240 beyond the suprachoroidal space SCS (i.e., into the retinaR). In this manner, the injection assembly can assist the user indetermining the location of the distal end of the needle 7240 such thatcommunication of the medicament into a layer of the eye other than thetarget layer (i.e., the suprachoroidal space SCS) can be prevented.Furthermore, the needle adjustment mechanism 7230 can assist the user inprecisely controlling the excursion length of the needle 7240, therebyeliminating the use of excessive force and/or preventing over excursionof the needle 7240 beyond the target layer (i.e., the suprachoroidalspace SCS).

In some embodiments, the hub 7270 or any of the hubs described hereincan be constructed from a relatively soft material, which can bewell-suited to forming a fluid-tight seal. For example, in someembodiments, the system 7000, or any other system described herein canbe used to deliver a medicament through the skin of a user (e.g., forintravenous or intramuscular delivery of the medicament). In suchembodiments, the hub 7270 or any other hub described herein can have astiffness less than the stratum corneum that forms the top layer of theskin. The distal end surface 7275 of the hub 7270 or any other hubdescribed herein can deform about the stratum corneum as a force isapplied on the system 7000. In this manner, the sealing portion 7277defined by the distal end surface 7275 of the hub 7270 can form a fluidtight seal around the stratum corneum thereby preventing leakage of themedicament, an interstitial fluid, and/or blood from the injection site.In yet other embodiments, the hub 7270 can be constructed from multiplematerials. For example, in some embodiments, the distal end surface 7275of the hub 7270 can be constructed from and/or can include a layer orportion constructed from a material formulated to form a substantiallyfluid-tight seal with the outer surface of the target tissue (e.g., theconjunctiva C).

FIGS. 41A and 41B show a finite element analysis (FEA) model of thedistal portion 7274 of the hub 7270 compressed against the conjunctiva Cof the eye. In this model, a force of 1N is exerted on the hub 7270. Atthis force, the conjunctiva C is compressed by about 2 mm, which issubstantially equal to the total thickness of the conjunctiva C.Furthermore, the conjunctiva C conforms around the distal end surface7275 of the distal end portion 7274 of the hub 7270. As shown, thesealing portion 7277 of the distal end surface forms a substantiallyfluid-tight seal around the injection site of the needle 7240. The hub7270 was modeled as a rigid and inflexible member. However, the hub 7270or any other hub described herein can have any suitable stiffness basedon the material used to form the hub. In some embodiments, the hub 7270or any other hub described herein can have a stiffness substantiallysimilar to the stiffness of rubber, silicone, polymers, plastics (e.g.,polyethylene, polypropylene, polycarbonate, polytetrafluoroethylene,high density polyethylene, etc.), metals (e.g., aluminum, stainlesssteel, metal alloys, etc.), or any other material described herein.

FIGS. 42A-C shows a hub 8270, according to an embodiment. The hub 8270includes a proximal end portion 8272 and a distal end portion 8274. Theproximal end portion 8272 can configured to be coupled to a distal endof a housing (e.g., a distal end 3212 of the housing 3210 of the needleassembly 3200, or any other housing described herein) using any suitablecoupling mechanism, for example, friction-fit, threads, snap-fit,notches, grooves, indents, detents, any other suitable couplingmechanism or combination thereof. The hub 8270 defines a passageway 8276therethrough. At least a portion of a needle (e.g., the puncturingmember 3240, the needle 7240, or any other puncturing member describedherein) can be disposed within the passageway 8276, and can beconfigured to advance through the passageway 8276 out of the distal end8274. The distal end 8274 of the hub 8270 includes a contact surfacethat is curved, and for example, defines a convex or hemisphericalshape. The contact surface of the distal portion 8274 is configured to(i.e., has a size and/or shape configured to) contact an outer surfaceof a conjunctive of the eye and define a sealing portion that forms asubstantially fluid-tight seal around the insertion zone of thepuncturing member 8240 into a target tissue, for example, the eye. Thus,the hub 8270 can prevent leakage of the medicament, and/or bodily fluidfrom the insertion site, as described in with respect to the hub 7270included in the apparatus 7000.

In some embodiments, a hub can be substantially hollow and/or can definean enlarged lumen therethrough. Referring now to FIGS. 43A-C, a hub 9270includes a proximal end portion 9272, a distal end portion 9274, anddefines an internal volume 9275. The proximal end portion 9272 can beconfigured to be coupled to a distal end of a housing (e.g., the distalend 3214 of the housing 3210 included in the needle assembly 3200, orany other housing included in a needle assembly described herein). Forexample, a portion of a distal end of a housing (e.g., the housing 3210)can be configured to slide into the internal volume 9275. At least aportion of a needle (e.g., the puncturing member 3240, the needle 7240,or any other puncturing member described herein) can be disposed in theinternal volume 9275. In some embodiments, at least a portion of aneedle assembly, for example, the lead screw 3242 included in the needleassembly 3200 or any other component or any other needle assembly, canalso be disposed in the internal volume 9275. The distal end 9274 has acontact surface that is curved, for example, defines a convex or ahemispherical shape, such that the contact surface defines a sealingportion which can form a substantially fluid-tight seal around theinsertion zone of the puncturing member (e.g., the puncturing member3240, or the needle 7240), as described with respect to the hub 8270.The distal end 9274 defines an opening 9276 configured to enable atleast portion of the puncturing member (e.g., the puncturing member3240) to pass therethrough and into the ocular tissue of the eye.

In some embodiments, a hub can include one or more engagement structuresthat cooperatively function to surround the puncture member and/orcontact a surface of the target tissue. Moreover, in some embodiments, ahub can also be configured to induce deformation and/or movement of aportion of the target tissue when placed into contact with the targettissue. In such embodiments, the adjustment member can minimize“bunching” of the surface tissue (e.g., the conjunctiva). For example,FIGS. 44A and 44B are schematic illustrations of a portion of a deliverydevice 10000 in a first configuration and a second configuration,respectively, according to an embodiment. The delivery device 10000includes a hub 10270, a puncture member 10240 (also referred to hereinas a delivery member or a needle) and an engagement assembly 10280. Theengagement assembly 10280 includes a first elongate member 10281 and asecond elongate member 10285. The elongate members 10281, 10285 can beany suitable structure configured to engage the target tissue and deform(as described herein). For example, in some embodiments, the firstelongate member 10281 and/or the second elongate member 10285 can be athin structure (e.g., feeler gauge, wire, etc.). In some embodiments,the first elongate member 10281 and/or the second elongate member 10285can be any suitable structure configured to grip, hold, and/or deform aportion of the target tissue (e.g., the conjunctiva). Although notshown, additional elongate members (or “sleds”) can be coupled to thehub 10270. For example, in some embodiments, the hub 10270 can includethree elongate members attached thereto. In other embodiments, forexample, the hub 10270 can include more than three elongate members(e.g., four, five, or more elongate members) attached thereto.

As shown, a proximal end portion 10286 of the first elongate member10281 is coupled to the hub 10270. The first elongate member 10281 has acontact portion 10284 (e.g., the portion where the first elongate member10281 can contact a portion of the eye 10 shown in FIG. 1 , during use).The first elongate member 10281 has a distal end portion 10283. At leasta portion of the first elongate member 10281 can have a curved shape.The curved shape, for example, can be such that the contact portion10284 is configured to contact a portion of the eye (e.g., theconjunctiva) along a line tangent to a portion of the first elongatemember 10281. Further to this example, the curved shape of the portionof the first elongate member 10281 can allow for a desired distributionof force(s) to be applied to a portion of the eye during use. Forexample, in this manner the contact portion 10284 does not contact thesurface of the eye at a single point, but rather along a surface that isless likely to puncture the eye.

A proximal end portion 10286 of a second elongate member 10285 iscoupled to the hub 10270. The second elongate member 10285 has a contactportion 10288 (e.g., where the second elongate member 10285 contacts aportion of the eye 10 shown in FIG. 1 ). The second elongate member10285 has a distal end portion 10287. At least a portion of the secondelongate member 10285 can have a curved shape. The curved shape, forexample, can be such that the contact portion 10288 is configured tocontact a portion of the eye (e.g., the conjunctiva) along a linetangent to a portion of the second elongate member 10285. Further tothis example, the curved shape of the portion of the second elongatemember 10285 can allow for a desired distribution of force(s) to beapplied to a portion of the eye, as discussed above with respect to thefirst elongate member 10281.

When the delivery device 10000 is in a first configuration, as shown inFIG. 44A, the distal end portion 10283 of the first elongate member10281 and the distal end portion 10287 of the second elongate member10285 are separated by a distance A1. Similarly, in the firstconfiguration, the contact portion 10284 of the first elongate member10281 and the contact portion 10288 of the second elongate member 10285are separated by a distance B1. Moreover, when the delivery device 10000is in the first configuration, the distal tip of the puncture member10240 is spaced apart from the contact portion 10284 and/or the contactportion 10288 by a distance C1 taken along a center line of the puncturemember 10240, as shown in FIG. 44A. In some embodiments, the distal tipof the puncture member 10240 is spaced apart from a line defined by thecontact portion 10284 and the contact portion 10288 by a distance C1taken along a center line of the puncture member 10240.

In use, a user (e.g., a doctor, technician, nurse, physician,ophthalmologist, etc.) can manipulate a delivery device 10000 to insertthe puncture member 10240 into, for example, a portion of the eye (e.g.,the eye 10 shown in FIG. 1 ). In this manner, the user can apply adistal force to move the delivery device 10000 from the firstconfiguration to a second configuration. Similarly stated, when thepuncture member 10240 is inserted into the eye, the first elongatemember 10281 and the second elongate member 10285 can both move from thefirst configuration to the second configuration. When the deliverydevice 10000 is in the second configuration, as shown in FIG. 44B, thedistal end portion 10283 of the first elongate member 10281 and thedistal end portion 10287 of the second elongate member 10285 can beseparated by a distance A2, A2 being greater than A1. In the secondconfiguration, as shown in FIG. 44B, the contact portion 10284 of thefirst elongate member 10281 and the contact portion 10288 of the secondelongate member 10285 can be separated by a distance B2, B2 beinggreater than B1. Moreover, when the delivery device 10000 is in thesecond configuration, the distal tip of the puncture member 10240 isspaced apart from the contact portion 10284 and/or the contact portion10288 by a distance C2 taken along a center line of the puncture member10240, as shown in FIG. 44B, C2 being greater than C1. In someembodiments, the distal tip of the puncture member 10240 is spaced apartfrom a line defined by the contact portion 10284 and the contact portion10288 by a distance C2 taken along a center line of the puncture member10240, C2 being greater than C1 when the delivery device 10000 is in thesecond configuration.

In some embodiments, when the delivery device 10000 is moved from thefirst configuration to the second configuration, the contact portion10284 of the first elongate member 10281 and the contact portion 10288of the second elongate member 10285 can cause a portion of the eye tomove, or instead, prevent a portion of the eye from moving. Similarlystated, in some embodiments, the deformation of the first elongatemember 10281 and/or the second elongate member 10285 can move (oralternatively maintain a position of) a portion of the target tissue.For example, is some uses, at least one of the contact portion 10284 orthe contact portion 10288 can contact the conjunctiva of the eye. Inthis manner, at least one of the contact portions 10284, 10288 canstabilize, hold steady, grip, stretch, or mechanically fix a portion ofthe eye (e.g., the conjunctiva) when the device is moved from the firstconfiguration to the second configuration.

In some embodiments, the contact portions 10284, 10288 can create ataught spherical injection site. For example, the first elongate member10281 and/or the second elongate member 10285 can deform in a radialdirection from the center point (i.e., away from where the puncturemember 10280 penetrates) when the delivery device 10000 moves from thefirst configuration to the second configuration. In this manner, theconjunctiva can be held in a preferable position during the injection.In some instances, this can reduce the puncturing force to penetrate thesurface of the eye. In some embodiments, the “stretching” of theconjunctiva can minimize and/or eliminate any “bunching” of theconjunctiva that may otherwise occur, and instead can produce a surfacelayer (e.g., conjunctiva) having a substantially constant thickness. Insome instances, the contact portions 10284, 10288 can, at leasttemporarily, adhere to a portion of the surface layer (e.g.,conjunctiva). In this manner, the contact portions 10284, 10288 cancause movement of and/or stabilize at least a portion of the surfacelayer such that at least the portion of the surface layer is in apreferable position during the injection.

In some embodiments, the elongate member 10281 and/or the elongatemember 10285 can be attached to the hub 10270 in any suitable manner, asshown in FIGS. 44A and 44B. In yet other embodiments, the elongatemember 10281 and/or the elongate member 10285 can be coupled to anelongate member holder or interface (not shown). The elongate memberholder can be coupled to the hub 10270. In some embodiments, theelongate member holder (not shown) can be a ring.

The elongate members 10281, 10285 can be any suitable material (e.g.,metallic or plastic). In some embodiments, the sleds can contain aplurality of different materials. For example, the contact portion 10284of the first elongate member 10281 may contain a material not containedon a different portion of the first elongate member 10281. In someembodiments, for example, additional materials (e.g., a coating) can beapplied to any portion of the elongate members 10281, 10285. Further tothis example, the additional material can be configured to increase ordecrease friction between the elongate members 10281, 10285 and asurface layer (e.g., conjunctiva). In some embodiments, a plurality ofadditional materials can be applied to the elongate members 10281,10285. Each additional material (e.g., coating) from the plurality ofadditional materials, for example, can include relatively uniquematerial properties (e.g., viscosity, density, surface tension, etc.).

In some embodiments, the elongate members 10281, 10285 can provide anindicator associated with at least one of the distance A1, A2, B1, B2,C1, and/or C2. In some embodiments, the indicator can be a visualindicator such as a measuring scale, graduated marking or the like. Forexample, in some embodiments, the first elongate member 10281 caninclude indicia (e.g., lines, markings, tic marks, etc.). In someembodiments, the markings can represent a change in location of thedistal tip of the puncture member 10240 from the first configuration tothe second configuration. In yet another embodiment, the markings canrepresent a portion of the eye where the distal tip of the puncturemember 10240 is located. For example, the markings can indicate whetherthe distal tip of the puncture member 10240 is located in the sclera,choroid, suprachoroidal space, or retina of the eye. For anotherexample, the markings can indicate by term the location of the distaltip of the puncture member 10240 (e.g., sclera, choroid, suprachoroidalspace, retina, etc.), and can further indicate a location within thetermed location (e.g., a location within the choroid). In this manner,the markings can indicate, for example, the location of the distal tipof the puncture member 10240 relative to the sclera and/or the choroidwhen the distal tip is located within the suprachoroidal space.

Although shown as including multiple, deformable elongate members, inother embodiments an engagement assembly and/or an adjustment assembly,for example, included or coupled to a hub, can include a singledeformable member. For example, FIGS. 45A and 45B are schematicillustrations of a portion of a delivery device 11000, according to anembodiment. Specifically, FIG. 45A illustrates a portion of a deliverydevice 11000 in a first configuration and a second configuration (e.g.,illustrated with dashed lines), and FIG. 45B illustrates a bottom viewof the portion of the delivery device 11000. The delivery device 11000includes a hub 11270, a puncture member 11240 (also referred to hereinas a delivery member or a needle) and an engagement member 11280. Theengagement member 11280 can be any suitable structure configured toengage the target tissue.

As shown, a proximal portion 11282 of the engagement member 11280 iscoupled to the delivery device 11000. The engagement member 11280 iscoupled to the delivery device 11000 via the hub 11270. In yet otherembodiments, the engagement member 11280 can be coupled to an engagementmember holder (not shown). The engagement member holder can then becoupled to the hub 11270. The engagement member 11280 has a contactportion 11284.

When the delivery device 11000 is in a first configuration, as shown, inFIG. 45A, a portion of the contact portion 11284 of the engagementmember 11280 is spaced apart from the distal tip of the puncture member11240 by a distance A1 taken along a center line of the puncture member11240. In some embodiments, the distal tip of the puncture member 11240is spaced apart from a line defined by the contact portion 11282 of theengagement member 11280 by a distance A1 taken along a center line ofthe puncture member 11240. In use, a user (e.g., a doctor, technician,nurse, physician, ophthalmologist, etc.) can manipulate a deliverydevice (not shown) to insert the puncture member 11240 into, forexample, a portion of the eye (e.g., the eye 10 shown in FIG. 1 ). Inthis manner, the user can apply a distal force to move the deliverydevice 11000 from the first configuration to a second configuration.Similarly stated, when the puncture member 11240 is inserted into theeye, the engagement member 11280 can move from the first configurationto the second configuration, as illustrated by the dashed line in FIG.45A. When the delivery device 11000 is in the second configuration, asshown in FIG. 44A, a portion of the contact portion 11284 of theengagement member 11280 and the distal tip of the puncture member 11240are separated by a distance A2 (see the distance indicated from thedashed lines), A2 being greater than A1. In some embodiments, when thedelivery device 11000 is in the second configuration, the distal tip ofthe puncture member 11240 is spaced apart from a line defined by thecontact portion 11284 of the engagement member 11280 by a distance A2taken along a center line of the puncture member 11240, A2 being greaterthan A1.

In some embodiments, when the delivery device 11000 is moved from thefirst configuration to the second configuration, the contact portion11284 can cause a portion of the eye to move, or instead, prevent aportion of the eye from moving. Similarly stated, in some embodiments,the deformation of the engagement member 11280 can move (oralternatively maintain a position of) a portion of the target tissue.For example, in some uses, the contact portion 11282 of the engagementmember 11280 can stabilize, hold steady, grip, stretch, or mechanicallyfix a portion of the eye (e.g., the conjunctiva) when the deliverydevice 11000 is moved from the first configuration into the secondconfiguration.

Although the engagement member 11280 is shown and described above asincluding a contact portion 11284 that is curved in a convex manner(i.e., curved outwardly, or in a manner that resembles an outer surfaceof a sphere), in other embodiments, a hub and/or an engagement membercan include a contact portion that is curved in a concave manner (i.e.,curved inwardly, or in a manner that resembles an inner surface of asphere).

In some embodiments, the engagement member 11280 can deform at avariable rate. For example, the engagement member 11280 can providevariable resistance when a user manipulates the delivery device 11000.In some embodiments, the engagement member 11280 can provide a hard stop(i.e., a user would be substantially prevented from further insertingthe puncture member 11240 into a portion of the eye). In yet otherembodiments, the engagement member 11280 can be configured to providevariable resistance based on its level of deformity. In this manner, theengagement member 11280 can be configured to provide a first level ofresistance when the puncture member 11240 is in a first portion of theeye and a second level of resistance when the puncture member 11240 isin a second portion of the eye, the first level of resistance beingdifferent than the second level of resistance. In some embodiments, forexample, the first portion of the eye can be the sclera and the secondportion of the eye can be the suprachoroidal space.

In some embodiments, the engagement member 11000 can provide anindicator associated with at least one of the distance A1 or A2 (i.e.,the depth of penetration of the puncture member 11240). In someembodiments, the indicator can be a visual indicator such as a measuringscale, graduated marking or the like. For example, in some embodiments,the engagement member 11280 can include indicia (e.g., lines, markings,tic marks, etc.). In some embodiments, the markings can represent achange in location of the distal tip of the puncture member 11240 fromthe first configuration to the second configuration. In yet otherembodiments, the markings can represent a portion of the eye where thedistal tip of the puncture member 11240 is located. For example, themarkings can indicate whether the distal tip of the puncture member11240 is located in the sclera, choroid, suprachoroidal space, or retinaof the eye. For another example, the markings can indicate by theanatomical term the location of the distal tip of the puncture member11240 (e.g., sclera, choroid, suprachoroidal space, retina, etc.) andcan further indicate a location within the termed location (e.g., alocation within the choroid). In this manner, the markings can indicate,for example, the location of the distal tip of the puncture member 11240relative to the sclera and/or the choroid when the distal tip is locatedwithin the suprachoroidal space.

Although the engagement assembly 10000 is shown and described above asincluding two or more elongate members having contact portions that arecurved in a convex manner (i.e., curved outwardly, or in a manner thatresembles an outer surface of a sphere), in other embodiments, a hub, anengagement assembly and/or adjustment member can include a contactportion or surface that is curved in a concave manner (i.e., curvedinwardly, or in a manner that resembles an inner surface of a sphere).Similarly stated, in some embodiments, a delivery device can include ahub, an engagement assembly and/or adjustment member having a surfacethat is configured to engage, fit and/or conform to the surface of thetarget tissue (e.g., the eye). As one example, FIGS. 46-47 areperspective views of a portion of a delivery device according to anembodiment. In particular, FIGS. 46-47 are perspective views of anengagement member 12280 configured to be used in conjunction with any ofthe delivery devices shown and described herein. The engagement member12280 includes a proximal end portion 12281 and a distal end portion12282 and defines a lumen or passageway therebetween.

The proximal end portion 12281 of the engagement member 12280 can becoupled to a delivery device (not shown in FIG. 46 ). In someembodiments, the proximal end portion 12281 of the engagement member12280 can be coupled to the hub 10270 (not shown in FIGS. 45-46 ), orany other hub described herein. For example, in some embodiments, theengagement member 12280 can be threadedly coupled to a hub to control aneffective length of a puncture member (also referred to as a deliverymember or needle) as described above. In this manner, the engagementmember 12280 can perform the function of a needle adjustment mechanism.

As shown in FIGS. 46 and 47 , the distal end portion 12282 of theengagement member 12280 includes three contact members 12283. Each ofthe contact members 12283 has a surface that includes an inverse-dimpledor “beaded” traction pattern 12284. The contact members 12283 areconfigured to contact a surface of the target tissue (e.g., theconjunctiva of the eye) during use to facilitate insertion of a puncturemember (not shown) and/or injection of a drug formulation into thetarget tissue. The distal end portion 12282 of the engagement member12280 and/or the contact members 12283 can be any suitable structureconfigured to engage the target tissue (as described herein). Forexample, in some embodiments, the distal end portion 12282 of theengagement member 12280 and/or the contact members 12283 can be anysuitable structure configured to grip, hold, and/or deform a portion ofthe target tissue (e.g., the conjunctiva of the eye). As shown, at leasta portion of the distal end portion 12282 and/or the contact members12283 have a curved shape. The curved shape, for example, can be suchthat the contact members 12283 are configured to contact a portion ofthe eye (e.g., the conjunctiva) along a line tangent to a portion of thecontact members 12283. Further to this example, the curved shape of theportion of the contact members 12283 can allow for a desireddistribution of force(s) to be applied to a portion of the eye.

In some embodiments, the contact members 12283 can create a taughtspherical injection site. For example, the contact members 12283 candeform in a radial direction from the center point (i.e., away fromwhere the puncture member penetrates) when the delivery device (notshown) moves from a first configuration to a second configuration. Inthis manner, the conjunctiva can be moved into and/or held in apreferable position during the injection. In some instances, this canreduce the puncturing forces to penetrate the surface of the eye. Insome embodiments, the “stretching” of the conjunctiva can minimizeand/or eliminate any “bunching” of the conjunctiva that may otherwiseoccur, and instead can produce a surface layer (e.g., conjunctiva)having a substantially constant thickness. In some instances, thecontact members 12283 can, at least temporarily, adhere to a portion ofthe surface layer (e.g., the conjunctiva). In this manner, the contactmembers 12283 can cause movement of and/or stabilize at least a portionof the surface layer such that at least the portion of the surface layeris in a preferable position during the injection.

In some embodiments, the engagement member 12280 (and any of theengagement and/or adjustment members shown and described herein) canform a substantially fluid-tight seal and/or a substantiallyliquid-tight seal with the outer surface of the target tissue (e.g., theconjunctiva of the eye). In this manner, leakage of the injectedmedicament along the needle track during the injection event can bereduced and/or eliminated. Expanding further, in some embodiments, theanatomy of the target tissue and/or the arrangement of the deliverydevice can be such that, in use, a portion of the opening of the needle(not shown) may be placed in fluid communication with the suprachoroidalspace (e.g., suprachoroidal space 36 in FIG. 1 ) of the eye, whileanother portion of the opening of the needle may be positioned withinthe sclera 20 (e.g., sclera 20 in FIG. 1 ). Thus, when the drugformulation is conveyed into the eye via the needle (not shown), aportion of the drug formulation may be prone to migrating away from thedesired region (e.g., the suprachoroidal space 36 in FIG. 1 ) and out ofthe eye via the needle track. By forming a substantially fluid-tightseal and/or a substantially liquid-tight seal, the engagement member12280 (e.g., the surface of the contact members 12283) can produce anarea of high resistance to flow, thus minimizing and/or eliminating theflow migration and/or leakage.

In some embodiments, the engagement member 12280 can be constructed froma relatively soft material, which can be well-suited to forming afluid-tight seal. In yet other embodiments, the engagement member 12280can be constructed from multiple materials. For example, in someembodiments, the contact members 12283 of the engagement member 12280can be constructed from and/or can include a layer or portionconstructed from a material formulated to form a substantiallyfluid-tight seal with the outer surface of the target tissue (e.g., theconjunctiva). Although the contact members 12283 are shown and describedabove as including a beaded surface, in other embodiments, the contactmembers 883 can include any suitable surface features. For example, asshown in FIG. 48 , in some embodiments, an engagement member 13280 caninclude a series of contact members 13283 having a smooth surface. Asanother example, as shown in FIG. 49 , in some embodiments, anengagement member 14280 can include a series of contact members 14283having a ridged and/or stepped surface. In other embodiments, forexample, an engagement member can include a contact member having aribbed surface (e.g., similar to that shown in FIG. 52 ).

In other embodiments, an engagement member and/or contact members caninclude any combination of suitable surface features. In this manner,for example, an engagement member can include a first contact memberwith a smooth surface and a second contact member with a ribbed surface.As another example, a contact member can include a first portion havinga ribbed surface and a second portion having a beaded surface.

Although shown as including three contact members, in other embodiments,an engagement member, hub and/or adjustment member can include anynumber of contact members. For example, FIGS. 50-55 are illustrations ofdelivery devices according to various embodiments. In particular, FIG.50 is a perspective view of an engagement member 15280 according to someembodiments. FIG. 51 is a perspective view of an engagement member 16280according to some embodiments. As shown, for example in FIGS. 50 and 51, in some embodiments, the engagement member 15280, 16280 can includecontact members 15283, 16283 that are curved in a spherical manner.Further to this example, in some embodiments, the contact member 15283can include a dimpled surface (e.g., FIG. 50 ). In yet otherembodiments, for example, the contact member 16283 can include a smoothsurface (e.g., FIG. 51 ). FIG. 52 is a perspective view of an engagementmember 17280 according to some embodiments. FIG. 53 is a perspectiveview of an engagement member 18280 according to some embodiments. Asshown, for example in FIGS. 52 and 53 , in some embodiments, theengagement member 17280, 18280 can include contact members 17283, 18283that are curved in a planar manner. Further to this example, in someembodiments, the contact member 172823 can include a ribbed surface(e.g., FIG. 52 ). In yet other embodiments, for example, the contactmember 18283 can include a smooth surface (e.g., FIG. 53 ). FIG. 54shows a perspective view of the engagement member 18280 in use with adelivery device 18000 to engage an eye and/or deliver a medicamentthereto, according to an embodiment. The delivery device can be similarto the delivery device 100, 400, 1000, 2000, 3000, 7000, or any otherdelivery device or medical injector described herein. FIG. 55 shows across-sectional view of the perspective view shown in FIG. 54 . Thedelivery device 18000 includes a hub 18270, a puncture member 18240(also referred to herein as a delivery member or a needle) and anengagement member 18280.

In use, a user (e.g., a doctor, technician, nurse, physician,ophthalmologist, etc.) can manipulate the delivery device 18000 toinsert the puncture member 18240 into, for example, a portion of the eye(e.g., the eye 10 shown in FIG. 1 ). In this manner, the user can applya distal force such that puncture member 18240 is advanced distallyrelative to and/or through the engagement member 18280 (e.g., as shownby arrow F1 along longitudinal axis AA in FIG. 55 ). In this manner, aportion of the puncture member 11080 can be advanced through a portionof the eye.

In some embodiments, a system for ocular injection can include any ofthe hubs described herein and/or a drug extraction device configured tomatingly engage with a housing and/or a medicament delivery container.For example, referring now to FIGS. 56-71 , in some embodiments, asystem 19000 can include housing 19110, an actuator 19320, an actuatingmember 19140, a medicament containment chamber 19310, a hub 19270, aneedle 19240, and a cap 19280. The system 19000 can be configured todeliver a substance, for example, a medicament to a target tissue, forexample, the SCS of an eye.

The housing 19110 (FIG. 57 ) includes a first portion 19110 a, and asecond portion 19110 b (collectively “19110”) that can be coupledtogether to define an internal region for housing at least a portion ofthe medicament containment chamber 19310 and the actuator 19320. Thehousing 19110 includes a gripping portion 19112 to allow a user to gripthe housing 19110 between his index and middle finger. The housing 19110also includes ridges 19114 to allow easy gripping of the housing 19110by the user. For example, the user can grip the gripping portion 19112with one hand and grip the ridges 19114 with the fingers of a secondhand during injection, for example, delivery of a medicament into atarget tissue (e.g., ocular tissue). In this manner, the user anysideways movement of the system 19000 during medicament delivery can bereduced. A set of windows 19116 are defined in a sidewall of the housing19110. The set of windows 19116 can be configured to allow the user toview the interior volume of the medicament containment chamber 19310,for example, to view a level of a medicament remaining in the medicamentcontainment chamber 19310. The housing 19110 also include a set of slots19118, each slot configured to slidably receive a rib 19323 included inan engagement portion 19322 of the actuator 19320, such that the set ofslots are configured to keep the actuator 19320 aligned as the actuator19320 is displaced within the housing 19110 and the medicamentcontainment chamber 19310.

As shown in FIGS. 57 and 58 , the actuator 19320 includes an engagementportion 19322 and a plunger portion 19324. The engagement portion 19322includes a set of ribs 19323 slidably disposed in the set of slots 19118of the housing 19110, as described before. A portion of the engagementportion 19322 is disposed in a cavity 19146 defined by the actuatingmember 19140 (see, e.g., FIG. 62 ). The plunger portion 19324 includes aprotrusion 19327 disposed on a distal end of the actuator 19320. Theprotrusion 19327 can be configured to be disposed in a recess 19335defined by a plug 19328 with close tolerance (e.g., friction fit), asdescribed herein. The plug 19328 (FIGS. 59-60 ) is disposed in theinternal volume 19316 defined by the medicament containment chamber19310. The plug 19328 includes a proximal end 19332 coupled to theplunger portion 19324 of the actuator 19320 and a distal end 19334 influid communication with a medicament or any other liquid disposed inthe internal volume 19316 defined by the medicament containment chamber19310. The plug 19328 can be made of a rigid but soft material, forexample, rubber, and includes the recess 19335 configured to receive theprotrusion 19327 of the actuator 19320 with close tolerance (e.g.,friction fit). The plug 19328 includes a first sidewall 19336 a and asecond sidewall 19336 b (collectively referred to as the “sidewalls19336) in contact with a sidewall of the internal volume 19316 of themedicament containment chamber 19310. The sidewalls 19336 form asubstantially fluid-tight seal with the sidewalls of the inner volume19316 defined by the medicament containment chamber 19310. In thismanner, the plug 19328 can prevent leakage of the liquid medicament fromthe internal volume 19316, for example, leakage of the medicament into aportion of the internal volume 19316 within which the plunger portion19324 of the actuator 19320 is disposed.

The actuation member 19140 (FIGS. 61-62 ) includes a depression 19142,shaped to conform to a thumb of a user, for example, to allow easydisplacement of the actuating member 19140 by the user. The actuatingmember 19140 also includes ridges 19144 configured to allow easygripping of the actuating member 19140, for example, when loading amedicament into the medicament containment chamber 19310. The actuationmember 19140 also includes a cavity 19146, configured to slidablyreceive a portion of the engagement portion 19322 of the actuator 19320with close tolerance (e.g., friction fit). In some embodiments, theactuating member 19140 can be configured to be engaged by the user tomanually move the plunger portion 19324 of the actuator 19320 within theinternal volume 19316 of the medicament containment chamber 19310. Insome embodiments, the actuating member 19140 can be included in aninjection assembly, for example, the injection assembly 100, 2100, orany other injection assembly described herein, that can be included inthe system 19000. The actuating member 19140 can be configured toactivate the injection assembly, for example, to release and/or move theactuator 19320 such that the plunger portion 19324 moves within theinternal volume 19316 and expels at least a portion of the medicamentthrough the needle 19240 (e.g., into the SCS of the eye).

As shown in FIGS. 63-65 , the medicament containment chamber 19310defines an internal volume 19316, configured to house a medicament. Themedicament containment chamber 19310 includes a delivery portion 19324.A first set of threads 19318 a and a second set of threads 19318 b (FIG.63 ) are formed on an outer wall of the delivery portion 19314. Saidanother way, the outer wall of the delivery portion 19314 includesdouble-start threads. The threads 19318 are configured to allow couplingof the medicament containment chamber 19310 to a coupling portion 19272of the hub 19270. In some embodiments, any other hub, an injection sitemarker, for example, the injection site marker 20280 described below,and/or an extraction device, for example extraction device 21280, can becoupled to the delivery portion 19324 via the threads 19318. Thedelivery portion 19314 includes a first cavity 19315 configured toreceive an engagement portion 19273 (e.g., a nozzle) of the hub 19270,such that a fluidic channel 19317 included in the delivery portion 19314is in fluid communication with a first fluidic channel 19277 included inthe engagement portion 19273 of the hub 19270. The medicamentcontainment chamber 19310 also includes a second cavity 19313. Theengagement portion 19322 of the actuator 19320 is disposed within thesecond cavity 19313 and is configured to be slidably displaced withinthe second cavity 19313.

As shown in FIGS. 66-67 , the hub 19270 includes an engagement portion19273, a coupling portion 19272, and a delivery portion 19274. An innersidewall of the engagement portion 19273 and an outer sidewall of thecoupling portion 19272 define a recess 19275 configured to receive thedelivery portion 19314 of the medicament containment chamber 19310. Theinner sidewall of the coupling portion 19272 includes threads 19278,configured to engage the threads 19318 a and/or 19318 b of themedicament containment chamber 19310, thereby coupling the hub 19270 tothe medicament containment chamber 19310. An outer sidewall of thecoupling portion 19272 includes a set of ridges 19276. The ridges 19276can facilitate a user to grip the hub 19270, for example, for couplingor uncoupling the hub 19270 from the medicament containment chamber19230. The engagement portion 19273, defines a fluidic channel 19277configured to engage the fluidic channel 19317 of the medicamentcontainment chamber 19130 and establish fluidic communication betweenthe medicament containment chamber 19130 and the hub 19270. The deliveryportion 19274, defines a second fluidic channel 19279 configured toremovably receive the needle 19240, for example, a microneedle (e.g.,any suitable microneedle described herein). The needle 19240 isconfigured to be disposed within a target tissue, for example, oculartissue and defines a lumen 19241 such that the needle 19240 isconfigured to establish fluidic communication between the medicamentcontainment chamber 19310 and the portion of the user's body (e.g., theeye). In some embodiments, the needle 19240 can be fixedly disposed inthe second fluidic channel 19279. In some embodiments, the needle 19240can be monolithically formed with the hub 19270 such that the secondfluidic channel 19279 and the lumen of the needle 19241 are continuouslyand/or seamlessly formed.

As shown in FIGS. 68 and 69 , the cap 19280 includes a coupling portion19282 that includes a first cavity 19283 configured to slidably receivethe coupling portion 19272 of the hub 19270. A set of grooves 19285 isformed on an inner sidewall of the coupling portion 19282 configured tomate with the set of ridges 19276 of the hub 19270 with close tolerance(e.g., friction fit). The cap 19280 also includes an engagement portion19284 that defines a second cavity 19284 configured to receive thedelivery portion 19274 of the hub 19270. At least a portion of an outersidewall of the engagement portion 19284 is substantially flat, forexample, to allow a user to grip the cap 19280 with ease (e.g., tocouple or uncouple the hub 19270 from the medicament containment chamber1150). The cap 19280 can thus enable safe coupling/uncoupling of hub19270 to the medicament containment chamber 19310 and/or preventaccidental piercing of a portion of a user's body by the needle 19240during handling of the system 19000.

Referring now to FIGS. 70-71 , FIG. 70 shows the system 19000 in a firstconfiguration, such that the actuator 19320 and the actuating member19140 are in a first position and the internal volume 19316 of themedicament containment chamber 19310 is at least partially filled withthe medicament. A user can now engage the actuating member 19140 byapplying a force in the direction shown by the arrow F on the actuatingmember 19140, for example, using a thumb of the user. This urges theactuator 19320, which is coupled to the actuating member 19140, todisplace along a longitudinal axis AA of the system 19000 and urge thesystem 19000 into the second configuration as shown in FIG. 71 . In thesecond configuration, the actuator 19320 is displaced from the firstposition to a second position within the internal volume 19316 of themedicament containment chamber 19310. This displacement causes the plug19328, which is in fluid communication with the medicament, to slidefrom the first position to the second position within the internalvolume 19316. The movement expels the medicament from the internalvolume 19316 into the fluidic channel 19277 of the hub 19270, andfurther through the lumen 19241 of the needle 19240 into the targettissue (e.g., the eye).

In some embodiments, a system for ocular injection can include aninjection marker for marking an injection site on a target tissue, forexample, ocular tissue. FIG. 72-73 show perspective views of aninjection site marker 20280 according to an embodiment. As shown, aproximal end 20282 of the injection site marker 20280 can be coupled toa delivery device, for example, coupled to the coupling portion 19272 ofthe hub 19270 included in the system 19000. The injection site marker20280 has a distal end 20284, which includes a set of protrusions 20286disposed on a distal end surface of the distal end 20284. In someembodiments, the proximal end 20282 of the injection site marker 20280can be used in conjunction with and/or coupled to any of the hubs,engagement members and/or adjustment members described herein. Forexample, in some embodiments, the injection site marker 20280 can bethreadedly coupled to a hub of a delivery device (e.g., hub 19270 ofdelivery device 19000). In other embodiments, for example, the injectionsite marker 20280 can be coupled by way of friction (e.g., interferencefit, press fit, friction fit, etc.)

In some embodiments, the protrusions 20286 of the distal end 20284 ofthe injection site marker 20280 can be configured to contact a portionof the eye (e.g., the eye 10 shown in FIG. 1 ). In some embodiments, forexample, the protrusions 20286 of the injection site marker 20280 can beconfigured leave a marking on a portion of the eye. The marking, forexample, can indicate an injection site. For example, the markings canappear as parallel indentations on the conjunctiva of the eye indicatingto the user that the injection is to be performed in the region betweenthe parallel markings. Further to this example, in some embodiments, theinjection site marker 20280 can be removably coupled to a deliverydevice (e.g., the delivery device 19000). In such embodiments, theinjection site marker 20280 can be removed from the delivery deviceafter marking the injection site on the target tissue. A needle assemblyand/or hub that includes a needle, for example, the needle 19240 coupledthereto, can then be coupled to the delivery device which can be used todeliver the medicament to the injection site marked by the injectionsite marker 20280. In some embodiments, an injection site marker candefine a passageway to allow a needle to pass therethrough. In suchembodiments, the injection site marker can remain coupled to thedelivery device during delivery of the medicament to the target tissue.

In some embodiments, a system for delivering medicaments can include anextraction device for extracting medicaments or any other fluid from acontainer, for example, a vial. Referring now to FIG. 74-80 , a system21000 includes a housing 21110, an actuator (not shown), an actuatingmember 21140, a medicament containment chamber 21310, and an extractionmember 21280. The system 21000, that includes the extraction member21280, can be used to extract a liquid medicament from a medicamentcontainer 21294. The housing 21110, the actuator, the medicamentcontainment chamber 21310, and actuating member 21140 of the system21000 can be substantially similar in structure and function to thecomponents of the system 19000 described earlier, and are therefore notdescribed in further detail herein.

FIG. 74 shows the extraction member 21280 uncoupled from the medicamentcontainment chamber 21310 while FIG. 75 shows the extraction member21280 coupled to the medicament containment chamber 21310. As shown inFIG. 76 , the extraction member 21280 includes a coupling portion 21281,an engagement portion 21284 and an extraction portion 21288. Threads21282 are formed on an inner side wall of the coupling portion that areconfigured to mate with the threads of 21318 a and 21318 b of themedicament containment chamber 21310 and to couple the extraction member21280 to the medicament containment chamber 21310. A set of ridges 21283are formed on an outer sidewall of the coupling portion 21281. Theridges 21283 can, for example, serve as grips to facilitate a user tocouple/uncouple the extraction member 21280 to the medicamentcontainment chamber 21250. The inner sidewall of the coupling portion21281 and an outer sidewall of the engagement portion 21284 define acavity 21285, configured to receive a portion of the medicamentcontainment chamber 21310, when the extraction member 21280 is coupledto the medicament containment chamber 21310. The engagement portion21284 includes a fluidic channel 21286 configured to establish fluidcommunication between the extraction member 21280 and the medicamentcontainment chamber 21250, for example, to allow communication of fluidfrom the extraction member 21280 (e.g., liquid medicament extracted froma medicament vial) to the medicament containment chamber 21250.

The extraction portion 21288 is configured to be releasably coupled to acontainer a container 21294 that contains a medicament, and establishfluid communication between the container 21294 and the medicamentcontainment chamber 21310 via the extraction member 21280. Theextraction portion 21288 includes a set of arms 21289. Each of the setof arms 21289 has an angled portion configured to flex open forreceiving a cap of the container, for example, the container 21294. Eachof the set of arms 21289 also include a ledge 21290 configured to securethe cap of the container, for example container 21294 when the containeris coupled to the extraction member 21280, as shown in FIG. 75 . Theextraction portion 21288 also includes a puncturing member 21291 thatdefines a fluidic channel 21292. The puncturing member 21291 isconfigured to puncture a seal of a container, for example, container21294, and establish fluid communication between the container and themedicament containment chamber 21310, via the extraction member 21280,as described herein.

FIG. 77 shows a perspective view of the system 21000 in a firstconfiguration, such that the container 21294 is uncoupled from theextraction member 21280. The container 21294 includes a cap 21296 thathas a seal 21297, for example, a septum (e.g., a rubber septum), anddefines an internal volume for housing a liquid medicament. FIG. 78shows a sectioned view of the perspective view shown in FIG. 77 , butonly the extraction member 21280 and the container 21294 are shown forclarity. A user can apply a force shown by the arrow F₂ (FIG. 78 ) alonga longitudinal axis BB of the system 21000 to urge the extraction member21280 towards the container 21294. Optionally, a force can also beapplied to the container 21294 to urge the container 21294 towards theextraction member 21280. This urges the system 21000 into the secondconfiguration (FIGS. 79-80 ) such that extraction member 21280 isreleasably coupled to the cap 1296 of the container 21294. As shown inthe sectioned view of FIG. 80 , in the second configuration a surface ofthe ledge 21290 included in the each of the set of arms 21289 of theextraction member 21280, are contacting a small portion of a bottomsurface of the cap 21296 of the container 21294. In this manner, thecontainer 21294 is releasably secured to the extraction member 21280.Furthermore, the puncturing member 21291 punctures the seal 21297 of thecap 21296 included in the container 21294 to establish fluidcommunication between the container 21294 and the medicament containmentchamber 21310 via the extraction member 21280. Medicament can now beextracted from the container 21294 by a user by engaging the actuatingmember 21240, as described herein with reference to system 19000 (FIGS.70-71 ). To uncouple the container 21294 from the extraction member21280, the user can simple pull the container 21294 away from theextraction member in a direction opposing the direction indicated byarrow F2 (FIG. 78 ).

In some embodiments, a system for injection of a medicament into anocular tissue, for example, the SCS can include a mechanism forinsertion of the puncturing member as well as delivering the medicament.Referring now to FIGS. 81-83 , a system 22000 includes a housing 22110,a needle assembly 22200 that includes a puncturing member 22240 and ahub 22270, and a medicament containment chamber 22310. At least aportion of an actuator (not shown) can be disposed in the medicamentcontainment chamber 22310. The actuator is configured to communicate amedicament disposed in an internal volume of the medicament containmentchamber 22310 into an ocular tissue, for example, the SCS of an eye.

The housing 22110 has an ergonomic shape and includes ridges 22114 toallow a user to easily grip the housing 22110. The housing 22110 candefine an internal volume within which at least a portion of themedicament containment chamber 22310 and the actuator can be disposed.In some embodiments, an injector assembly, for example, the injectorassembly 2100 or any other injector assembly described herein can bedisposed in the housing 22110. The housing 22110 is configured to movelaterally along a longitudinal axis A_(L) of the system 22000, between afirst configuration shown in FIG. 81 and a second configuration shown inFIG. 83 . In this manner, the housing 22110 can move the actuator anddraw in or expel out a medicament from the medicament containmentchamber 22310. In some embodiments, the housing 22110 can also beconfigured to insert the puncturing member 22240 into the ocular tissue.

The medicament containment chamber 22310 defines an internal volumewithin which a medicament can be disposed. A set of markings 22315 canbe defined on an outer surface of the medicament containment chamber22310. The medicament containment chamber 22310 can be substantiallytransparent such that the user can visually observe a volume of themedicament disposed in the internal volume and use the markings 22315 todetermine the quantity of the remaining medicament. In some embodiments,the medicament containment chamber 22310 can be substantially similar tothe medicament containment chamber 1310, 2310, 3310, or any othermedicament containment chamber described herein.

The needle assembly 22200 includes a housing 22210 that can define aninternal volume configured to house the components of the needleassembly 22200. A plurality of ridges 22216 are disposed on an outersurface of the housing 22210. The ridges 22216 are configured to allow auser to easily grip the housing 22210 (e.g., for rotating the housing22210). The needle assembly 22200 can be configured to adjust a lengthof the puncturing member 22240 protruding from a distal end 22274 of thehub 22270. For example, a user can rotate the needle assembly 22200about the longitudinal axis A_(L) to adjust a length of the puncturingmember 22240 protruding from a distal end 22272 of the hub 22270. Insome embodiments, the needle assembly 22200 can include an adjustmentmember, a lead screw, bushing, bearing, locking pin, markings, or anyother components as described with respect to the needle assembly 3200described herein.

The puncturing member 22240 is configured to be inserted into the eyeand to deliver a medicament into the eye. The puncturing member 22240can be substantially similar to the puncturing member 3240 or any otherpuncturing member described herein. At least a portion of the puncturingmember 22240 is disposed in the hub 22270. For example, a proximal endportion of the puncturing member 22240 can be disposed in a passagewaydefined by the hub 22270. The hub 22270 includes a proximal end 22272and a distal end 22274. The distal end 22274 can be curved, for example,define a convex or hemispherical shape. A distal end surface of thedistal end 22274 can define a sealing portion configured to contact anouter surface of the eye, for example, the conjunctiva, and form asubstantially fluid-tight seal around an insertion site of thepuncturing member 22240, as described with respect to the hub 7270. Theproximal end 22272 of the hub 22270 can be removably or fixedly coupledto a distal portion of the housing 22210. For example, the proximal end22272 can include a friction fit, snap fit, threads, grooves, notches,indents, detents, or any other suitable coupling mechanism to couple thehub 22270 to the housing 22210. In some embodiments, the hub 3270, 7270,8270, 9270, or any other hub described herein can be coupled to thehousing 22210.

In a first configuration shown in FIG. 81 , the housing 22210 can bedisposed distally relative to the needle assembly 22200 and themedicament containment chamber 22310. The medicament can be disposed inthe internal volume of the medicament containment chamber 22310. In thesecond configuration, shown in FIG. 83 , a user can dispose the hub22270 of the system 22000 on an outer layer of the eye (e.g., theconjunctiva C). The user can then exert a force on the housing 22110 inthe direction shown by the arrow F3 to move the housing 22110 proximallyrelative to the needle assembly 22200. This can cause the puncturingmember 22240 to be inserted into the ocular tissue, for example, asclera of the eye, and the medicament to be expelled from the internalvolume of the medicament containment chamber 22310. The user can use theneedle assembly 22200 to adjust an insertion depth of the puncturingmember 22240 to ensure that the medicament is communicated to the targetocular tissue (e.g., the SCS).

In some embodiments, a needle adjustment mechanism can include adjustingthe insertion depth of a needle into a target tissue, for example,ocular tissue, by varying the force on an actuation rod included in amedical injector. For example, FIGS. 84A and 84B show a portion of amedical injector 23000, that includes an actuation rod 23320 and aneedle disposed in a target tissue in a first configuration and a secondconfiguration, respectively, according to an embodiment. A distal endportion of the actuation rod 23320 is disposed in a medicament containerincluded in the medical injector. The medical injector can besubstantially similar to the medicament container 130, 1310, 2310, 3310,or any other medicament container described herein. The needle 23240 canbe any suitable puncture member, for example, a microneedle (e.g., a 27gauge needle, a 30 gauge needle, or even smaller). The medical injector23000 also includes a needle adjustment mechanism that can be used toadjust the distance a distal tip of the needle 23240 travels into thetarget tissue, for example, ocular tissue based on the magnitude offorce applied on an proximal portion, for example, an engagement portionof the actuation rod 23320. By way of example, in some embodiments, theneedle adjustment assembly can include any suitable mechanism configuredto increase the distance that the distal tip of the needle 23240 travelsinto the target tissue based on the force applied on the actuation rod23320. The force applied on the actuation rod 23320 can continue toincrease the distance travelled by the distal tip of the needle 23240without delivering the medicament from the distal tip of the needle23240, until the distal tip of the needle 23240 is disposed within atarget region (e.g., the SCS) of the target tissue. The force can then,for example, overcome the backpressure of the target region of thetarget tissue such that the distal tip of the needle 23240 does nottravel any further into the target tissue and the medicament isdelivered to the target region. The needle adjustment mechanism caninclude any suitable components such as, for example, a biasing member(e.g., a spring or a hydraulic biasing member), one or more valves, and,or a force sensing mechanism. In some embodiments, the force applied onthe actuation rod 23320 can be adjusted manually, for example, viahaptic feedback to a user engaging the actuation rod 23320. In someembodiments, an automated force adjustment mechanism, for example,included in the needle adjustment mechanism or an injection assembly(e.g., the injection assembly 100, 2100, or any other injection assemblydescribed herein) can be used to adjust the force and thereby, controlthe insertion depth of the distal tip of the needle 23240.

For example, the distal tip of the needle 23240 can be inserted into anocular tissue and configured to deliver a medicament to the SCS of theocular tissue. In the first configuration shown in FIG. 84A, a firstforce F₁ is applied on the actuation rod 23320. The first force F1(e.g., less than about 2N) can be sufficient to overcome thebackpressure of the conjunctiva (not shown) and get inserted into thesclera S, but insufficient to urge the distal tip of the needle 23240 totravel across the thickness of the sclera S and be disposed in the SCS.The user can then apply a second force F₂ greater than the first forceF₁ and sufficient to overcome a backpressure and/or density of thesclera S such that the distal tip of the needle 23240 travels throughthe sclera S and is disposed within or near the SCS. In someembodiments, the second F₂ can be between about 2 N and about 6 N, forexample, about 3 N, about 4 N, about 5 N, or any other range or valuetherebetween. The user can maintain the force F₂ such that once thedistal tip of the needle 23240 reaches the SCS, the force F₂ canovercome the backpressure of the SCS and thereby, deliver the medicamentto the SCS. In some embodiments, the transition from the first force F1to the second force F₂ can be gradual. For example, the force applied onthe actuator can be increased slowly from the force F₁ until the forcehas a sufficient magnitude (e.g., substantially equal to the secondforce F₂) to urge the distal tip of the needle 23240 to travel throughthe sclera S and be disposed in the SCS.

In some embodiments, a medical injector can include an injectionassembly that includes an actuation member configured to actuate anactuation rod included in the medical injector. For example, FIGS. 85Aand 85B show a medical injector 24000 that includes medicamentcontainer, a needle, and an injection assembly, in a first and a secondconfiguration respectively, according to an embodiment. The injectionassembly includes an actuation member 24120 and an actuation rod 24320.The injection assembly can include other components such as, forexample, an energy storage member (e.g., a spring, a compressed gascylinder, or a propellant container), a release member (e.g., a lock,latch, a pawl), a guide rod, or any other components described withrespect to the injection assembly 100, 2100, or any other injectionassembly described herein. In some embodiments, the actuation member24120 can be configured to engage and/or secure a proximal end portionof the actuation rod 24320. In some embodiments, the actuation member24120 can be configured to engage a release member that is configured toengage or otherwise secure a proximal end portion of the actuation rod24120. The actuation member 24120 can be engaged by a user such that theactuation member 24120 releases the actuation rod 24320 or urges therelease member to release the actuation rod 24320. This can enable adistal end portion of the actuation rod 24320 to move within themedicament container, as shown in FIG. 85B.

For example, as shown in FIG. 84A-B, the actuation member 24120 includesa lever like member that can be disposed on a sidewall of a housingcoupled to the medicament container. In the first configuration shown inFIG. 84A, the actuation member can be a in a first position in which adistal end of the actuation member 24120 is distally disposed from themedicament container. In the first configuration, a proximal end portionof the actuation member 24120 can be engaged by the actuation member24120 or the release member and prevent a distal end portion of theactuation rod 24320 from moving within the medicament container.Furthermore, an energy storage member or a biasing member can be coupledto the proximal end portion of the actuation rod 24320. In the secondconfiguration shown in FIG. 84B, a user can engage the actuation member24120, for example, move a distal end of the actuation member 24120proximally relative to the medicament containment chamber in a directionshown by the arrow A. This can urge the actuation member to release theproximal end portion of the actuation rod 24320. In some embodiments,the engaging of the actuation member 24120 can engage a release memberengaging or otherwise securing the proximal end portion of the actuationrod 2320 such that the release member releases the proximal end portionof the actuation rod 24320. The energy storage member or biasing membercoupled to the proximal end portion of the actuation rod 24320 can thenurge the distal end portion of the actuation rod 24320 to move withinthe medicament container and thereby, deliver medicament to a targettissue via the needle.

In some embodiments, a medical injector can include a needle adjustmentmechanism that includes a wheel. For example, FIG. 86 shows a medicalinjector 25000 that can include a medicament container, a needleassembly 25200, and a needle 25240. The needle adjustment mechanism25200 includes a wheel 25230. The wheel 25230 is pivotally mounted in ahousing of the medical injector 25000. The wheel 25230 can include aplurality of protrusions defined thereon, which can be engaged by a userto move or otherwise rotate the wheel 25230. The wheel 25230 can beconfigured to be rotated in discrete angular displacements, such thateach discrete angular displacement corresponds to a discrete adjustmentof the length of a portion of the needle 25240 emerging from a distalend of a housing, or a hub coupled to the housing. In some embodiments,each discrete angular displacement can correspond to a length adjustmentof about 100 microns of the needle 25240. In this manner, the wheel25230 can allow for digital adjustment of the length of the needle25240. For example, a user can insert a distal tip of the needle a firstdistance (e.g. corresponding to the depth of the sclera) of a targettissue (e.g., ocular tissue). The user can then engage the wheel 25230by rotating the wheel 25230 about its pivot mount in discrete incrementsas described herein. This can adjust the length of the needle 25240 suchthat a distal tip of the needle 25240 travels a second distance into thetarget tissue (e.g., corresponding to the depth of the SCS) such thatthe distal tip of the needle 25240 is disposed within or near a targetregion (e.g., the SCS) of the target tissue. The medical injector 25000can deliver at least a portion of the medicament disposed within themedicament container into the target tissue (e.g., the SCS). Forexample, an injection assembly (e.g., the injection assembly 100, 2100,or any other injection assembly described herein) included in themedical injector 25000 can be configured to initiate delivery of themedicament into the target region (e.g., the SCS), thereby informing theuser that the distal tip of the needle 25240 is disposed in the targetregion. In some embodiments, the wheel 25230 can also be configured tomove a distal end of an actuation rod disposed within the medicamentcontainer, for example, to deliver the medicament to the target tissuevia the needle 25240.

In some embodiments, a medical injector can include a pressure assistassembly configured to exert a pressure on a proximal end portion of anactuation rod and assist, facilitate and/or affect the delivery of amedicament from a medicament container. For example, FIG. 87 shows aportion of a medical injector 26000 that includes a housing 26110, apressure assist assembly that includes an actuation member 26120, and amedicament container 26310 coupled to the housing 26110. A needle isalso coupled to the medicament container 26310 and in fluidiccommunication with a medicament disposed within the medicament container26310. As shown, in some embodiments, the actuation member 26120 can bea button disposed within a sidewall of the housing 26110. The pressureassist assembly can also include other components such as, for example,one or more energy storage members (e.g., a spring, a compressed gascontainer, or a propellant container). The energy storage member can becoupled to a proximal end portion of an actuation rod included in themedical injector 26000. A distal end portion of the actuation rod can bedisposed within the medicament container 26310 and configured to movewithin the medicament container 26310. In some embodiments, the pressureassist assembly can also include a release member configured to engageor otherwise secure the proximal end portion of the actuation rod in afirst configuration in which the medicament container is filled with avolume of the medicament. In such embodiments, the actuation member26120 can be configured to engage the release member and urge therelease member to release the proximal end portion of the actuation rod.For example, in a second configuration, the actuation member 26120 canbe engaged (e.g., depressed) by a user thereby urging the release memberto release the proximal end portion of the actuation rod. The energystorage member can now exert a force on the proximal end portion of theactuation rod configured to move a distal end portion of the actuationrod within the medicament container 26310. This applies a pressure onthe medicament disposed within the medicament container 26310 anddispels the medicament through a distal end of the needle.

In some embodiments, a medical injector can include a needle adjustmentmechanism that includes a leaf spring. For example, FIG. 88 shows aportion of a medical injector 27000 that includes a medicament container27310, a leaf spring 27230, and a needle 27240 in a first position(solid lines) and a second configuration (dotted lines). The leaf spring27230 can be coupled to the medicament container 27310 or a hub coupledto the medicament container 27310, and configured to move from a firstposition to a second position in response to a force applied in adirection shown by the arrow F. The movement of the leaf spring 27230 isconfigured to allow a distal tip of the needle 27240 to be disposedwithin a target region. More force can be required to move the leafspring 27230 more and move the distal tip of the needle deeper into thetarget tissue (e.g., an ocular tissue). For example, as shown in FIG. 88, in the first configuration a distal end surface of the leaf spring27230 can be in contact with the outer surface of the conjunctiva C ofan eye. Furthermore, a limbus 27242 defined on a distal end of theneedle 27240 can be disposed a first distance L₁ into the eye asmeasured form a distal end of the leaf spring 27230 such that the limbus27242 is disposed in the sclera S of the eye. A force F can be appliedto move or otherwise compress the leaf spring 27230 and move the limbus27242 deeper into the eye. For example, a magnitude of the force F canbe increased until the leaf spring 27230 moves into the secondconfiguration. This also urges the distal end of the needle 27240 tomove deeper into the eye, until in the second configuration, the limbus27242 is disposed a second distance L₂ into the eye as measured from thedistal end of the leaf spring 27230. The second distance L₂ cancorrespond to a depth of the suprachoroidal space within the eye, suchthat the limbus 27242 is disposed within or near the suprachoroidalspace SCS (e.g., the target region) in the second configuration. In thismanner, the leaf spring 27230 can be used to adjust a length of theneedle 27240 thereby, facilitating delivery of a medicament to thetarget region of a target tissue. In some embodiments, the movement ofthe leaf spring 27230 from the first position to the second position canbe configured to move the needle a predetermined distance correspondingto the depth of a target region of a target tissue (e.g., the SCS).

In some embodiments, a needle adjustment mechanism can include anadjustment member movable between a first position and a second positionto adjust a distance a distal tip of a needle travels within a targettissue. For example, FIGS. 89A and 89B show a portion of a medicalinjector 28000 that includes a medicament container 28310, a hub 28270,an adjustment member 28230 and a needle 28240 in a first configurationand a second configuration, respectively. The medicament container 28310can be substantially similar to the medicament container 130, 1310,2310, 3310, or any other medicament container described herein. Theproximal end portion of the hub 28270 can be coupled to the medicamentcontainer 28310 and a distal end portion of the hub 28270 can be coupledto a proximal end of the needle 28240 such that a medicament containedwithin the medicament container 28310 is in fluid communication with theneedle 28240. The hub 28270 can be substantially similar to the hub7270, 8270, 9270, or any other hub described herein. The adjustmentmember 28230 can be slidably disposed about the needle 28240 and beconfigured to be movable between a first position A and a secondposition B. As shown, the adjustment member 28230 defines a curvedsurface, which can be configured to conform the curved surface of atarget tissue, for example, an eye. The movement of the adjustmentmember 28230 can be used to adjust a distance that a distal tip of theneedle 28240 can be inserted into the target tissue, for example, oculartissue.

For example, in the first configuration shown in FIG. 89A, theadjustment member 28230 can be disposed at the first position A and adistal tip of the needle 28240 can be inserted a first distance into atarget tissue (e.g., within the sclera of an eye). Furthermore, thecurved surface of the adjustment member 28230 can be in contact with andconformal to an outer surface of the target tissue (e.g., theconjunctiva of the eye). A force can be applied on the medical injector28000, for example, on a proximal end portion of the medicamentcontainer 28310, or a proximal end portion of an actuation rod includedin the medical injector 28000. This can urge the adjustment member 28230to slide and move about the needle 28240 proximally relative to themedicament container 28310. The force can be maintained until theadjustment member 28230 moves to position B. This increases the distancethe distal tip of the needle 28240 travels within the target tissue(e.g., ocular tissue), for example, until the distal tip of the needle28240 is disposed within or near a target region (e.g., the SCS) of thetarget tissue. In this manner, the medicament disposed within themedicament container 28310 can be delivered to the target region (e.g.,the SCS) of the target tissue.

In some embodiments, a needle adjustment assembly can include anadjustment member configured to adjust the length of a needle indiscrete increments. For example, FIGS. 90A-C show a medical injector29000 that includes a medicament container 29310, a needle adjustmentassembly 29200, and a needle 29240 fluidically coupled to the medicamentcontainer 29310, in a first, second, and third configuration, accordingto an embodiment. The medicament container 29310 can be substantiallysimilar to the medicament container 130, 1310, 2310, 3310, or any othermedicament container described herein. The needle 29240 can include anysuitable puncture member, for example, a microneedle, or any otherneedle described herein. The needle adjustment mechanism 29200 includesan adjustment member 29230 configured to be engaged by a user to adjusta length of the needle 29240, for example, to a control a distance adistal tip of the needle 29240 travels into a target tissue. By way ofexample, the adjustment member 29230 can be configured to move indiscrete increments, for example, increments of 100 microns such thatthe length of the needle 29240 can be digitally adjusted. For example,as shown in the first configuration of FIG. 90A, the needle can have afirst length L₁ (e.g., about 750 microns) measured from a distal tip ofthe needle to a distal end of the medicament container 29310, or a hub(e.g., any of the hubs described herein) coupled to the distal end ofthe medicament container 29310. The length L₁ can be sufficient toinsert the distal tip of the needle 29240 in a target tissue such thatthe distal tip is disposed short of a target region (e.g., the SCS) ofthe target tissue (e.g., ocular tissue). The adjustment member 29230 canbe engaged, for example, depressed into the medicament chamber by afirst increment by applying a force F on the adjustment member 29230.This can increase the length of the needle 29240 to a second length L₂(e.g., about 850 microns), as shown in FIG. 90B measured from the distaltip of the needle 29240 to the distal end of the medicament container29310, or a hub (e.g., any of the hubs described herein) coupled to thedistal end of the medicament container 29310. The second length L₂ canbe sufficient to insert the distal tip of the needle 29240 deeper intothe target tissue but still insufficient to dispose the distal tip ofthe needle 29240 into the target tissue. The adjustment member 29230 canbe engaged a second time applying the force F again on the adjustmentmember 29230. This can further increase the length of the needle 29240to a third length L₃ (e.g., about 950 microns) measured from the distaltip of the needle 29240 to the distal end of the medicament container29310, as shown in FIG. 90C. The third length L₃ can be sufficient toinsert the distal tip of the needle 29240 deeper into the target tissuesuch that the distal tip of the needle 29240 is disposed within thetarget region (e.g., the SCS) of the target tissue. Thus, delivery ofthe medicament contained within the medicament container 29310 can beinitiated to the target region (e.g., the SCS) of the target tissue, forexample, via an injection assembly included in the medical injector29000.

In some embodiments, a medical injector can include a needle adjustmentmechanism configured to allow adjustment of a length of a needleincluded in the medical injector in a small set of qualitativeincrements. For example, FIG. 91 shows a medical injector 30000 thatincludes a needle adjustment mechanism including an adjustment member30230, and a needle 30240 fluidically coupled to a medicament container.The adjustment member 30230 is slidably disposed within a sidewall of ahousing of the medical injector 30000. The adjustment member 30230 canbe configured to be moved between three discrete positions correspondingto a short length, an intermediate (mid) length, and a long length ofthe needle emerging from a distal end of the medical injector 30000. Theneedle adjustment mechanism can include other components such as, forexample, notches, grooves, indents, detents, a lock ball, a biasingmember, or any other component configured to allow the adjustment member30230 to be moved in the discrete increments as described herein.

In some embodiments, a medical injector can include a hub configured toallow adjustment of a length of a needle inserted into a target tissue.For example, FIGS. 92A and 92 B show a portion of a medical injector31000 that includes a housing 31110, a hub 31270, and a needle 31240,according to an embodiment. The needle 31240 is fixedly coupled to adistal end of the housing 31110, for example, fluidically coupled with amedicament container disposed within the housing 31110. The hub 31270 iscoupled to a distal end portion of the housing 31110 such that thedistal end portion can move within a passageway defined by the hub31270. Furthermore, the distal end portion of the hub 31270 can define acurved surface configured to conform to a curved surface of a targettissue, for example, an eye. The housing 31110 includes a first ridge31114 a and a second ridge 31114 b configured to be matingly disposedwithin a groove 31272 defined on an inner surface of the hub 31270.While shown as including two ridges, the housing 31110 can include anynumber of ridges disposed thereon for example, 3, 4, 5, or even more.Furthermore, the hub 31270 can be formed from a flexible material, forexample, rubber, plastics, polymers, or any other flexible materialdescribed herein. This can enable the ridges 31114 from sliding out ofthe groove 31272 into the channel defined by the hub 31270 byapplication of a force on the housing 31110. In this manner, either thefirst groove 31114 a or the second groove 31114 b can be mated with thegroove 31272 to adjust the length of the needle 31240.

For example, as shown in FIG. 92B, in a first configuration the hub31270 can be disposed on a conjunctiva of an eye, such that the curvedsurface of the distal end portion of the hub 31270 conformally contactsthe curved conjunctiva. In the first configuration, the first ridge31114 a can be disposed in the groove 31272 such that a distal tip ofthe needle 31240 is not inserted into the eye. A force can be exerted onthe housing 31110 to displace the housing 31110 within the channeldefined by the hub 31270 while maintaining the curved surface of the hub31270 in contact with the conjunctiva. This can urge the medicalinjector 31000 into a second configuration in which the second ridge31114 b is disposed within the groove 31272. The moving of the housing31110 can also urge the needle 31240 to move within the channel definedby the hub 31270 until a distal tip of the needle 31240 pierces the eye.The distal tip of the needle 31240 can continue travelling into the eyetissue until the second ridge 31114 b is disposed in the groove 31272.In some embodiments, the distal tip of the needle 31240 can be disposedwithin a target region, for example, the SCS in the secondconfiguration. In some embodiments, the distal tip of the needle 31240can be disposed near but not within the target region, for example, theSCS of the eye. In such embodiments, the user can increase the force onthe housing 31110 to insert the distal tip of the needle 31240 furtherinto the eye, for example, by a flexing of the sidewalls of the hub,such that the distal tip of the needle 31240 can be disposed within thetarget region (e.g., the SCS) of the target tissue.

In some embodiments, a medical injector can include a hub configured tocontact an outer surface of the target tissue and flex or bend to allowa needle included in the medical injector to be inserted into the targettissue. For example, FIG. 93A shows a perspective view of a portion of amedical injector 32000. The medical injector includes a hub 32270, amedicament container 32310 and needle 32240 that can be fluidicallycoupled to a medicament container included in the medical injector32000. The hub 33270 is coupled to a distal end portion of themedicament container 32310. The hub 32270 has a hemispherical or asemi-hemispherical shape and defines a region therewithin. The hub 32270is configured to be disposed on the distal end portion of the housing32110 such that the needle 32240 is disposed within the region definedby the hub 32270. A distal end surface of the hub 32240 is configured tocontact an outer surface of a target tissue, for example, theconjunctiva of an eye. Furthermore, the hub 32270 can be formed from aflexible material, for example, rubber, plastic, polymers, silicone, orany flexible material described herein or a combination thereof. The hub32270 is configured to flex or bend, for example, by application of aforce on the medicament container 32110. The bending or otherwiseflexing can reduce the distance between a distal tip of the needle 32240and the target tissue, such that the distal tip of the needle 32240 canbe disposed within the target tissue.

For example, FIGS. 93B and 93C show the medical injector 32000 in afirst configuration and a second configuration, respectively. In thefirst configuration, the distal end surface of the hub 32270 is disposedon a target tissue, for example, the conjunctiva of the eye such that adistal tip of the needle 32240 is distal from the outer surface of thetarget tissue. Said another way, in the first configuration no force isexerted on the hub 32270 such that the hub 32270 is not bent, and theneedle 32240 is not inserted into the target tissue. In the secondconfiguration, a force can be applied on the medicament container 32310,or any other portion of the medical injector 32000 such that the hubflexes or otherwise bends reducing the distance between the distal tipof the needle 32240 and the outer surface of the target tissue. Theforce can be maintained until the distal tip of the needle piercestarget tissue and is disposed within a target tissue (e.g., the SCS) ofthe target tissue (e.g., an eye).

In some embodiments, a medical injector can include a puncture memberincluded in a medical injector can be configured to sense light todetermine the depth of insertion of the puncture member. For example,FIGS. 94A and 94B show a portion of a puncture member 32240 that can beincluded in a medical injector, for example, the medical injector 100,1000, 2000, or any other medical injector described herein, in a firstconfiguration and a second configuration, respectively, according to anembodiment. The puncture member 32240 can be configured to communicatelight from the target tissue to a light sensor, for example, aphotodiode included in the medical injector. The puncture member 32240can be formed from any suitable optically transparent material, forexample, an optical fiber. A distal end of the optical fiber can bebeveled or otherwise formed into a sharp tip to pierce a target tissue.Furthermore, the distal tip can be optically transparent such that thepuncture member can communicate light from the target tissue to thelight sensor. The presence, absence, or otherwise amount of lightcommunicated by the puncture member 32240 to the sensor can be used todetermine the insertion depth and thereby, the region of the targettissue in which the distal end of the puncture member 32240 is disposed.

For example, in the first configuration shown in FIG. 94A, the distalend of the puncture member 32240 can be disposed in the sclera S of aneye. The sclera S is opaque so no light is communicated from thepuncture member 32240 to the light sensor. In the second configuration,the distal tip of the puncture member 32240 is inserted deeper into theocular tissue until at least a portion of the distal tip is disposedwithin the suprachoroidal space SCS which can be the target region fordelivering a medicament. Since the suprachoroidal space SCS istransparent, light entering the eye and impinging on the retina R alsopenetrates into the suprachoroidal space SCS. The light can becommunicated from the distal tip of the puncture member 32240 to thelight sensor included in the medical injector thus confirming that thedistal tip of the puncture member 32240 is indeed disposed in the targetregion of the eye. In some embodiments, the medical injector thatincludes the puncture member 32240 can alert a user that the distal tipof the puncture member 32240 is disposed within the suprachoroidal spaceSCS using an audible alert (e.g., a beep, an alarm, etc.), a hapticalert (e.g., vibrations, or minor electric current), or a visible alert(e.g., a light such as, for example, an LED light, or a visual message).Thus, a user can initiate delivery of the medicament through thepuncture member 32240 only when the distal tip of the puncture member32240 is within the suprachoroidal space SCS.

In some embodiments, a kit that includes a medical injector fordelivering a medicament to a target region of a target tissue caninclude all or parts of the concepts described herein. For example, insome embodiments, a kit can include a medical injector (e.g., themedical injector 10, 1000, 2000, 3000, 21000, or any other medicalinjector described herein), a transfer assembly that can include, forexample, an extraction member (e.g., the extraction member 21280), aninjection assist housing (e.g., the injection assembly 2100 or any otherinjection assembly described herein), a needle adjustment mechanism(e.g., the needle assembly 3200, or any other needle assembly describedherein), a container or vial of a substance, for example a medicament orany other substance described herein, replacement needles and/or hubs,one or more speculums, swabs, wipes, anti-biotic ointments, eye drops,or any other device or apparatus configured to facilitate delivery ofthe medicament to the target tissue, for example, the eye.

For example, FIG. 95 shows a speculum 33400 that can be included in akit that includes a medical injector 33000, according to an embodiment.The medical injector 33000 can be substantially similar to the medicalinjector 100, 1000, 2000, 3000, or any other medical injector describedherein. The speculum 33400 can be configured to be placed on an outersurface of the conjunctiva of the eye and open the eye lids of apatient. In this manner, the speculum 33400 can facilitate access to thesurface of the eye such that the medical injector can be used to delivera medicament to a target tissue of the eye, for example, the SCS. Thespeculum 33400 can include an ergonomic handle, which can be comfortablygripped by a user during use. The speculum 33400 also includes a cavity33410 configured to receive at least a portion of the medical injector33000. In use, a user can disposed the speculum 33400 on the conjunctivaof the eye such that the eyelids are forced open. Furthermore, thecavity 33410 can be located on a target portion of the eye. The user candispose a distal end portion of the medical injector 33000 into thecavity 33410 and deliver the medicament to a target region (e.g., theSCS) of the eye. In some embodiments, the cavity 33410 can be orientedsuch that a center line of a delivery passageway of the medical injector33000 and a surface line tangent of to the target surface of the eye(e.g., the conjunctiva, the sclera, and/or the suprachoroidal space SCS)defines an angle of entry of between about 75 degrees and about 105degrees, for example, about 90 degrees. Moreover, the cavity 33410 canbe configured to prevent lateral movement of the medical injector suchthat the centerline of the needle remains substantially normal to thetarget surface during delivery of the medicament.

In some embodiments, a speculum can include markings to enablemeasurement of a size, radius, diameter or otherwise cross-section of aneye. For example, FIG. 96 shows a speculum 34400 that can be included ina kit that includes a medical injector (e.g., the medical injector 100,1000, 2000, 3000, or any other medical injector described herein. Thespeculum 34400 includes two arms. A distal end portion of the each ofthe arms is configured to disposed on the first and the second eyelid.The distal end portions can be moved apart to open the eyelids and allowaccess to the surface of the eye. The distal portions also include aplurality of markings or indicia. The markings can be used to measure asize of the eye, for example, a size, radius, diameter, or otherwise,cross section of the eye. Information on the size of the eye can be usedto determine, for example, the thickness of individual layers, forexample, the sclera and the SCS. In this manner, a user can predict howfar a needle has to be penetrated into the eye such that a distal tip ofthe needle is disposed in a target region (e.g., the SCS) of the eye.

In some embodiments, a speculum can include mounting features to mount amedical injector. Referring now to FIG. 97 , a speculum 35400 includes aset of arms configured to open the eyelids of a patient and provideaccess to the eye. The speculum 35400 includes a mount 35410 configuredto receive mounting member 35114 included in a medical injector 35000.The medical injector 35000 can be substantially similar to the medicalinjector 100, 1000, 2000, 3000, or any other medicament containerdescribed herein. The mounting member 35410 can include any suitablemounting features, for example, a magnet, threads, snap-fit mechanism,friction-fit mechanism, or any other suitable mounting mechanismconfigured to mount the medical injector 35000 via the mounting member35114. In some embodiments, the mount 35114 can include a magnet. Insuch embodiments, the mounting member 35114 can be formed from amagnetic material, for example, a ferrous material, such that mountingmember 35114 can be coupled to the mount 35410 via magnetic coupling. Inuse, the speculum 35400 can be disposed on an eye of a patient. Each armof the speculum 35400 can be used to open an eyelid of the patient toallow access to the eye. The medical injector 35000 can be mounted onthe mount 35410 via the mounting feature 35114, for example, viamagnetic coupling. Mounting the medical injector 35000 can preventinadvertent movements of the medical injector 34000 during medicamentinjection thereby minimizing the risk of injury to the eye. Furthermore,the speculum 35400 can reduce the risk of an error by the user bypositioning the medical injector 35000 for the user so that the user canfocus on delivering the medicament to a target region of the eye insteadof correctly positioning the medical injector 35000 on the eye.

In some embodiments, a speculum can include a single piece speculum. Forexample, FIG. 98A shows a single piece speculum 36400 configured to bedisposed on a surface of an eye and open the eyelids of the patient. Thespeculum 36400 defines a cavity 36410 configured to receive at least aportion of a medical injector, for example, the medical injector 33000or any other medical injector described herein. For example, as shown inFIG. 98B, the speculum 36400 can be disposed on the eye such that thecavity 36410 is disposed over a target location of the eye. At least aportion of the medical injector 33000 is then disposed in the cavity36410 thereby positioning the medical injector 33000 over the targetlocation of the eye for delivering the medicament to a target regionwithin the target location.

FIG. 99 shows a schematic flow diagram of a method 500 for delivering amedicament to a target tissue using a medical injector that includes ahub having a convex distal end surface (e.g., the hub 7270, 8270, or thehub 9720), coupled thereto. The medical injector can include any of themedical injectors described herein. The method includes inserting adistal end portion of a needle of a medical injector into a targettissue to define a delivery passageway within the target tissue 502. Theneedle can include any suitable puncture member, for example, amicroneedle (e.g., a 27 gauge needle, a 30 gauge needle, or evensmaller), or any other puncture member described herein. In someembodiments, the target tissue can be ocular tissue including theconjunctiva, the sclera, and the suprachoroidal space. In someembodiments, the inserting is performed such that centerline of thedelivery passageway and a surface line tangent to the target surfacedefines an angle of entry of between about 75 degrees and about 105degrees, for example, about 90 degrees. In some embodiments, theinserting can be performed such that the centerline of the needle issubstantially normal to the target surface. This can, for example,minimize tissue damage and provide the shortest path for a distal tip ofthe needle to reach a target region of the target tissue (e.g., theSCS). Next, the convex distal end surface of the hub is placed incontact with a target surface of the target tissue to fluidicallyisolate the delivery passageway 504. In some embodiments, the placingcan include deforming the target surface. For example, the distal endsurface of the hub can include a sealing portion configured to contactand define a substantially fluid-tight seal with the target surface, forexample, the conjunctiva of the eye (e.g., as defined with respect tothe sealing portion 7277 included in the hub 7270). In such embodiments,the sealing portion can be substantially symmetrical around a centerlineof the needle. In some embodiments, the sealing portion can be convex.In some embodiments, only a portion of the sealing portion can beconfigured to contact the target surface of the target tissue to formthe substantially fluid-tight seal. For example, a circular band of thesealing portion can contact the target surface and form thesubstantially fluid tight seal surrounding the centerline of the needle.

The method 500 further includes conveying, after the placing, asubstance into the target tissue via the needle 506. In someembodiments, the substance can include a medicament such as, forexample, a VEGF, a VEGF inhibitor, or a combination thereof. Thesubstance can be disposed within an internal volume of a medicamentcontainer included in the medical injector. An actuation rod can beincluded in the medical injector, which can be configured to be engagedby a user to fluidically communicate the substance from the medicamentcontainer to the target tissue via the needle. The medicament containerand the actuation rod can be substantially similar to the medicamentcontainer and/or the actuation rod included in the system 100, 1000,2000, 3000, or any other system or apparatus described herein. In someembodiments, the target tissue can be an eye, and the target surface canbe a conjunctiva of the eye. In such embodiments, the deliverypassageway can extend through a sclera of the eye such that theconveying includes conveying the substance into at least one of asuprachoroidal space or a lower portion of the sclera.

In some embodiments, the method 500 can further include adjusting,before the conveying, a length of the needle extending from the distalend surface of the hub. For example, the medical injector can include aneedle assembly, for example, the needle assembly 3200 or any otherneedle assembly described herein. The needle assembly can be used toadjust the length of the needle extending from the distal end surface ofthe hub until a distal tip of the needle is disposed within a targetregion, for example, the SCS of the eye. The substance, for example, asmedicament as described herein, can then be conveyed to the targetregion of the eye.

The embodiments described herein can be formed or constructed of one ormore biocompatible materials. Examples of suitable biocompatiblematerials include metals, glasses, ceramics, or polymers. Examples ofsuitable metals include pharmaceutical grade stainless steel, gold,titanium, nickel, iron, platinum, tin, chromium, copper, and alloysthereof The polymer may be biodegradable or non-biodegradable. Examplesof suitable biodegradable polymers include polylactides, polyglycolides,polylactide-co-glycolides (PLGA), polyanhydrides, polyorthoesters,polyetheresters, polycaprolactones, polyesteramides, poly(butyric acid),poly(valeric acid), polyurethanes and copolymers and blends thereof.Examples of non-biodegradable polymers include nylons, polyesters,polycarbonates, polyacrylates, polymers of ethylene-vinyl acetates andother acyl substituted cellulose acetates, non-degradable polyurethanes,polystyrenes, polyvinyl chloride, polyvinyl fluoride, poly(vinylimidazole), chlorosulphonate polyolefins, polyethylene oxide, blends andcopolymers thereof.

The microneedles described herein can be fabricated by a variety ofmethods. For example, in some embodiments, the hollow microneedle isfabricated using a laser or similar optical energy source. In oneexample, a microcannula may be cut using a laser to represent thedesired microneedle length. The laser may also be use to shape single ormultiple tip openings. Single or multiple cuts may be performed on asingle microncannula to shape the desired microneedle structure. In oneexample, the microcannula may be made of metal such as stainless steeland cut using a laser with a wavelength in the infrared region of thelight spectrum (0.7-300 μm). Further refinement may be performed usingmetal electropolishing techniques familiar to those in the field. Inanother embodiment, the microneedle length and optional bevel is formedby a physical grinding process, which for example may include grinding ametal cannula against a moving abrasive surface. The fabrication processmay further include precision grinding, micro-bead jet blasting andultrasonic cleaning to form the shape of the desired precise tip of themicroneedle.

A wide range of ocular diseases and disorders may be treated by themethods and devices described herein. Non-limiting examples of oculardiseases include uveitis, glaucoma, diabetic macular edema orretinopathy, macular degeneration, retinoblastoma, and genetic diseases.The methods described herein are particularly useful for the localdelivery of drugs that need to be administered to the posterior regionof the eye, for example the retinochoroidal tissue, macula, and opticnerve in the posterior segment of the eye. In one embodiment, thedelivery methods and devices described herein may be used in gene-basedtherapy applications. For example, the methods may administer a fluiddrug formulation into the suprachoroidal space to deliver select DNA,RNA, or oligonucleotides to targeted ocular tissues.

The microneedles can be used to target delivery to specific tissues orregions within the eye or in neighboring tissue. In various embodiments,the methods may be designed for drug delivery specifically to thesclera, the choroid, the Bruch's membrane, the retinal pigmentepithelium, the subretinal space, the retina, the macula, the opticdisk, the optic nerve, the ciliary body, the trabecular meshwork, theaqueous humor, the vitreous humor, and other ocular tissue orneighboring tissue in need of treatment.

A wide range of drugs may be formulated for delivery to ocular tissuesusing the present systems and devices described herein. Moreover, any ofthe delivery devices and/or methods described herein can involve,include and/or contain any of the drugs described herein. For example,in some embodiments, the medicament containment chamber 1310, 2310,3310, or any other medicament containment chamber can contain any of thedrugs and/or formulations described herein. As used herein, the term“drug” refers to any prophylactic, therapeutic, or diagnostic agent(e.g., a contrast agent). The drug may be selected from suitableproteins, peptides and fragments thereof, which can be naturallyoccurring, synthesized or recombinantly produced. Representativeexamples of types of drugs for delivery to ocular tissues includeantibodies, anti-viral agents, chemotherapeutic agents (e.g.,topoisomerase inhibitors), analgesics, anesthetics, aptamers,antihistamines, anti-inflammatory agents, and anti-neoplastic agents. Inone embodiment, the drug is triamcinolone or triamcinolone acetonide.

The term “antibody” is intended to refer broadly to any immunologicbinding agent such as IgG, IgM, IgA, IgD and IgE. An antibody can bemonoclonal or polyclonal, and in one embodiment, is a humanizedantibody. The term “antibody” is also used to refer to any antibody-likemolecule that has an antigen binding region, and includes antibodyfragments such as Fab′, Fab, F(ab′)2, single domain antibodies (DABs),Fv, scFv (single chain Fv), and engineering multivalent antibodyfragments such as dibodies, tribodies and multibodies. The techniquesfor preparing and using various antibody-based constructs and fragmentsare well known in the art (see, e.g., Antibodies: A Laboratory Manual,Cold Spring Harbor Laboratory, 1988; incorporated herein by reference).

Non-limiting examples of specific drugs and classes of drugs includeβ-adrenoceptor antagonists (e.g., carteolol, cetamolol, betaxolol,levobunolol, metipranolol, timolol), miotics (e.g., pilocarpine,carbachol, physostigmine), sympathomimetics (e.g., adrenaline,dipivefrine), carbonic anhydrase inhibitors (e.g., acetazolamide,dorzolamide), topoisomerase inhibitors (e.g., topotecan, irinotecan,camptothecin, lamellarin D, etoposide, teniposide, doxorubicin,mitoxantrone, amsacrine), prostaglandins, anti-microbial compounds,including anti-bacterials and anti-fungals (e.g., chloramphenicol,chlortetracycline, ciprofloxacin, framycetin, fusidic acid, gentamicin,neomycin, norfloxacin, ofloxacin, polymyxin, propamidine, tetracycline,tobramycin, quinolines), anti-viral compounds (e.g., acyclovir,cidofovir, idoxuridine, interferons), aldose reductase inhibitors,anti-inflammatory and/or anti-allergy compounds (e.g., steroidalcompounds such as betamethasone, clobetasone, dexamethasone,fluorometholone, hydrocortisone, prednisolone and non-steroidalcompounds such as antazoline, bromfenac, diclofenac, indomethacin,lodoxamide, saprofen, sodium cromoglycate), artificial tear/dry eyetherapies, local anesthetics (e.g., amethocaine, lignocaine,oxbuprocaine, proxymetacaine), cyclosporine, diclofenac, urogastrone andgrowth factors such as epidermal growth factor, mydriatics andcycloplegics, mitomycin C, and collagenase inhibitors and treatments ofage-related macular degeneration such as pegagtanib sodium, ranibizumab,aflibercept and bevacizumab.

In one embodiment, the drug is an integrin antagonist, a selectinantagonist, an adhesion molecule antagonist (e.g., intercellularadhesion molecule (ICAM)-1, ICAM-2, ICAM-3, platelet endothelialadhesion molecule (PCAM), vascular cell adhesion molecule (VCAM)), aleukocyte adhesion-inducing cytokine or growth factor antagonist (e.g.,tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), monocytechemotatic protein-1 (MCP-1), or a vascular endothelial growth factor(VEGF)). In some embodiments, a vascular endothelial growth factor(VEGF) inhibitor is administered with one of the microneedles describedherein. In some embodiments, two drugs are delivered by the methodsdescribed herein. The compounds may be administered in one formulation,or administered serially, in two separate formulations. For example,both a VEGF inhibitor and VEGF are provided. In some embodiments, theVEGF inhibitor is an antibody, for example a humanized monoclonalantibody. In further embodiments, the VEGF antibody is bevacizumab. Inanother embodiment, the VEGF inhibitor is ranibizumab, aflibercept orpegaptanib. In still other embodiments, the devices and methodsdescribed herein can be used to deliver one or more of the followingVEGF antagonists: AL8326, 2C3 antibody, AT001 antibody, HyBEV,bevacizumab (Avastin), ANG3070, APX003 antibody, APX004 antibody,ponatinib (AP24534), BDM-E, VGX100 antibody (VGX100 CIRCADIAN), VGX200(c-fos induced growth factor monoclonal antibody), VGX300, COSMIX,DLX903/1008 antibody, ENMD2076, Sutent (sunitinib malate), INDUS815C,R84 antibody, KDO19, NM3, allogenic mesenchymal precursor cells combinedwith an anti-VEGF agent or antibody, MGCD265, MG516, VEGF-Receptorkinase inhibitors, MP0260, NT503, anti-DLL4/VEGF bispecific antibody,PAN90806, Palomid 529, BD0801 antibody, XV615, lucitanib (AL3810,E3810), AMG706 (motesanib diphosphate), AAV2-sFLT01, soluble Flt1receptor, Cediranib (Recentin), AV-951 (Tivozanib, KRN-951), Stivarga(regorafenib), Volasertib (BI6727), CEP11981, KH903, Lenvatinib (E7080),terameprocol (EM1421), ranibizumab (Lucentis), Votrient (pazopanibhydrochloride), PF00337210, PRS050, SP01 (curcumin),Carboxyamidotriazole orotate, hydroxychloroquine, linifanib (ABT869,RG3635), Iluvien (fluocinolone acetonide), ALG1001, AGN150998, DARPinMP0112, AMG386, ponatinib (AP24534), AVA101, Vargatef (nintedanib),BMS690514, KH902, golvatinib (E7050), Afinitor (everolimus), Dovitiniblactate (TKI258, CHIR258), ORA101, ORA102, Axitinib (Inlyta, AG013736),Plitidepsin (Aplidin), Lenvatinib mesylate, PTC299, aflibercept(Zaltrap, Eylea), pegaptanib sodium (Macugen, LI900015), Visudyne(verteporfin), bucillamine (Rimatil, Lamin, Brimani, Lamit, Boomiq), R3antibody, AT001/r84 antibody, troponin (BLS0597), EG3306, vatalanib(PTK787), Bmab100, GSK2136773, Anti-VEGFR Alterase, Avila, CEP7055,CLT009, ESBA903, HuMax-VEGF antibody, GW654652, HMPL010, GEM220, HYB676,JNJ17029259, TAK593, XtendVEGF antibody, Nova21012, Nova21013, CP564959,Smart Anti-VEGF antibody, AG028262, AG13958, CVX241, SU14813, PRS055,PG501, PG545, PTI101, TG100948, ICS283, XL647, enzastaurin hydrochloride(LY317615), BC194, quinolines, COT601M06.1, COT604M06.2, MabionVEGF,SIR-Spheres coupled to anti-VEGF or VEGF-R antibody, Apatinib (YN968D1),and AL3818. In addition, delivery of a VEGF inhibitor or VEGF antagonistusing the microneedle devices and methods disclosed herein may becombined with one or more agents listed herein or with other agentsknown in the art.

In one embodiment, delivery of a VEGF antagonist to the suprachoroidalspace of the eye using the devices and methods disclosed herein is usedto treat, prevent and/or ameliorate a disease or disorder selected fromleukemia, relapsed/refractory leukemia, acute lymphoblastic leukemia,Acute myelogenous leukemia, relapsed or refractory acute myeloidleukemia, atopic dermatitis, recurrent or metastatic carcinoma of theurothelium, advanced urothelial carcinoma, blood disorders,myelofibrosis, brain tumor, glioblastoma, glioma, meningioma, cancer,carcinomatous meningitis (neoplastic meningitis), choroidalneovascularization (CNV), subfoveal choroidal neovascularization,chronic lymphocytic leukemia, chronic myelogenous leukemia, refractorychronic myelogenous leukemia, colon cancer, colorectal cancer,degenerative nerve diseases, Neurodegenerative diseases, diabeticmacular edema, visual Impairment due to diabetic macular edema, diabeticretinopathy, dry eye syndrome (inflammation and corneal tissue damage ofdry Eye), endometrial cancer, eye diseases, ocular diseases, ocularneovascularization, eye cancer, Neurofibromatosis Type II, head and neckcancer, hematological malignancies, Kaposi's Sarcoma, HepatocellularCarcinoma, Lung cancer, macular degeneration, age related maculardegeneration, exudative age-related macular degeneration, neovascular(wet) age-related macular degeneration (AMD)), subfoveal NeovascularAge-Related macular degeneration, macular edema, macular edemaassociated with Branch Retinal Vein Occlusion, macular edema followingretinal vein occlusion, macular edema with Retinal Vein Occlusion (RVO),multiple myeloma, relapsed or refractory multiple myeloma, multiplesclerosis, myopia, pathological myopia, neuroendocrine tumor, carcinoidtumor, neuroendocrine tumor, non-Hodgkin's Lymphoma, Diffuse LargeB-Cell Lymphoma, Non-Small-Cell Lung cancer, Non-Squamous Non-Small-CellLung cancer, Non-small-cell-lung Adenocarcinoma, Squamous Non-Small-CellLung cancer, corneal graft rejection, osteoarthritis, recurrentsymptomatic malignant ascites, peripheral T-cell lymphoma, androgenIndependent Psoriasis, pulmonary Fibrosis, Idiopathic PulmonaryFibrosis, respiratory diseases, retinal detachment, retinal disorders,retinitis pigmentosa, retinal vein occlusion, branch retinal veinocclusion, central retinal vein occlusion, rheumatoid arthritis,sarcoma, alveolar soft part sarcoma, soft tissue sarcoma,scleroderma/systemic sclerosis, solid tumors, refractory germ celltumors, thyroid cancer, differentiated or medullar thyroid cancer, andWest Syndrome (Infantile Spasm).

In certain embodiments, the drug delivered to the suprachoroidal spaceusing the devices and methods disclosed herein is rapamycin (Sirolimus,Rapamune). In one embodiment, the devices (e.g., microneedle devices)and methods disclosed herein are used in conjunction with rapamycin totreat, prevent and/or ameliorate a wide range of diseases or disordersincluding, but not limited to: abdominal neoplasms, acquiredimmunodeficiency syndrome, acute coronary syndrome, acute lymphoblasticleukemia, acute myelocytic leukemia, acute non-lymphoblastic leukemia,adenocarcinoma, adenoma, adenomyoepithelioma, adnexal diseases,anaplastic astrocytoma, anaplastic large cell lymphoma, anaplasticplasmacytoma, anemia, angina pectoris, angioimmunoblasticlymphadenopathy with dysproteinemia, angiomyolipoma, arterial occlusivediseases, arteriosclerosis, astrocytoma, atherosclerosis, autoimmunediseases, B-cell lymphomas, blood coagulation disorders, blood proteindisorders, bone cancer, bone marrow diseases, brain diseases, brainneoplasms, breast beoplasms, bronchial neoplasms, carcinoid syndrome,carcinoid Tumor, carcinoma, squamous cell carcinoma, central nervoussystem diseases, central nervous system neoplasms, choroid diseases,choroid plexus neoplasms, choroidal neovascularization, choroiditis,chronic lymphocytic leukemia, chronic myeloid leukemia, chronicmyelomonocytic leukemia, chronic myeloproliferative disorders, chronicneutrophilic leukemia, clear cell renal cell carcinoma, colonicdiseases, colonic neoplasms, colorectal neoplasms, coronary arterydisease, coronary disease, coronary Occlusion, coronary restenosis,coronary stenosis, coronary thrombosis, cutaneous T-cell lymphoma,diabetes mellitus, digestive system neoplasms, dry eye syndromes, eardiseases, edema, endocrine gland neoplasms, endocrine system diseases,endometrial neoplasms, Endometrial stromal tumors, Ewing's sarcoma,exanthema, eye neoplasms, fibrosis, follicular lymphoma,gastrointestinal diseases, gastrointestinal neoplasms, genitalneoplasms, glioblastoma, glioma, gliosarcoma, graft vs host disease,hematologic diseases, hematologic neoplasms, hemorrhagic disorders,hemostatic disorders, Hodgkin disease, Hodgkin lymphoma, homologouswasting disease, immunoblastic lymphadenopathy, immunologic deficiencysyndromes, immunoproliferative disorders, infarction, inflammation,intestinal diseases, intestinal neoplasms, ischemia, kidney cancer,kidney diseases, kidney neoplasms, leukemia, B-Cell, leukemia, lymphoid,liver cancer, liver diseases, lung diseases, lymphatic diseases,lymphoblastic lymphoma, lymphoma, macular degeneration, macular edema,melanoma, mouth neoplasms, multiple myeloma, myelodysplastic syndromes,myelofibrosis, myeloproliferative disorders, neuroectodermal tumors,neuroendocrine tumors, neuroepithelioma, neurofibroma, renal cancer,respiratory tract diseases, retinal degeneration, retinal diseases,retinal neoplasms, retinoblastoma, rhabdomyosarcoma, thoracic neoplasms,uveitis, vascular diseases, Waldenstrom Macroglobulinemia, and wetmacular degeneration. In addition, delivery of rapamycin using themicroneedle devices and methods disclosed herein may be combined withone or more agents listed herein or with other agents known in the art.

In one embodiment, the drug delivered to ocular tissue, for example thesclera or suprachoroidal space, using the microneedle devices andmethods disclosed herein reduces, inhibits, prevents and/or amelioratesinflammation. Examples of drugs that reduce, inhibit, prevent and/orameliorate inflammation include (but are not limited to): 19AV Agonists,19GJ agonists, 2MD Analogs, 4SC101, 4SC102, 57-57, 5-HT2 ReceptorAntagonist, 64G12, A804598, A967079, AAD2004, AB1010, AB224050,abatacept, Abegrin, Abevac, AbGn134, AbGn168, Abki, ABN912, ABR215062,ABR224050, Abrammune, Abreva, ABS15, ABS4, ABS6, ABT122, ABT325, ABT494,ABT874, ABT963, ABXIL8, ABXRB2, AC430, Accenetra, Acdeam, ACE772,Acebid, Acebloc, aceclofenac, acetaminophen, chlorzoxazone,serrapeptase, tizanidine hydrochloride, betadex, Aceclogesic Plus,Aceclon, Acecloren, Aceclorism, acecrona, Aceffein, acemetacin, Acenac,Acenterine, Acetal-SP, ibuprofen, Acetyl-G, acetylsalicylate dl-lysine,acetylsalicylic acid, Acicot, Acifine, Acik, Aclocen, Acloflam-P,Aclomore, Aclon, A-CQ, ACS15, actarit, Actemra, Acthelea liofilizado,Actifast, Actimab-B, Actiquim, Actirin, Actis PLUS, activated leukocytecell adhesion molecule antibody, Acular X, AD452, adalimumab, ADAMTS5Inhibitor, ADC1001, Adco-Diclofenac, Adco-Indomethacin, Adco-Meloxicam,Adco-Naproxen, Adco-Piroxicam, Adcort, Adco-Sulindac, adenosinetriphosphate disodium, AdenosineA2a Receptor Agonist, Adimod, Adinos,Adioct, Adiodol, Adipoplus, adipose derived stem and/or regenerativecells, Adizen, Adpep, Advacan, Advagraf, Advel, Adwiflam, AEB071,Aental, Afenac, Affen Plus, Afiancen, Afinitor, Aflamin, Aflazacort,Aflogen, Afloxan, AFM15, AFM16, AFM17, AFM23, Afpred-Dexa, AFX200,AG011, Agafen, aganirsen, AGI1096, Agidex, AGS010, Agudol, A-Hydrocort,AIK1, AIN457, Airtal, AIT110, AJM300, ajulemic acid, AK106, AL-24-2A1,AL4-1A1, Ala Cort, Alanz, Albumin immune-globulin, alclometasonedipropionate, ALD518, aldesleukin, Aldoderma, alefacept, alemtuzumab,Alequel, Alergolon, Alergosone, Aletraxon, Alfenac, Algason, Algin vekcoat, Algioflex, Algirex, Algivin Plus, alicaforsen sodium, Alin,Alinia, Aliviodol, Aliviosin, alkaline phosphatase, ALKS6931, allantoin,Allbupen, Allmol, Allochrysine, allogeneic endothelial cells, allogeneicmesenchymal precursor cells, allogeneic mesenchymal stem cells,alminoprofen, alpha 1 antitrypsin, Alpha 7 nicotinic agonists, alphaamylase, alpha chymotrypsin, alpha fetoprotein, alpha linolenic acid,Alpha-1-antitrypsin, Alpha2Beta1 Integrin Inhibitors, Alphacort,Alphafen, alpha-hexidine, alpha-trypsin, Alphintern, Alpinamed mobilityomega 3, Alpoxen, AL-Revl, Alterase, ALX0061, ALX0761, ALXN1007,ALXN1102, AM3840, AM3876, AMAB, AMAP102, Amason, Ambene, AmbezimG,amcinonide, AME133v, Amecin, Ameloteks, A-Methapred, Amevive, AMG108,AMG139, AMG162, AMG181, AMG191, AMG220, AMG623, AMG674, AMG714, AMG719,AMG729, AMG827, Amidol, amifampridine phosphate, Amifenac, Amimethacin,amiprilose hydrochloride, Amiprofen, Ammophos, Amoflam, AMP110, Ampikyy,Ampion, ampiroxicam, amtolmetin guacil, AMX256, AN6415, ANA004, ANA506,Anabu, Anacen, Anaflam, Anaflex ACI, Anaida, anakinra, Analgen Artritis,Anapan, Anaprox, Anavan, Anax, Anco, andrographis, Aneol, Anergix,Anervax.RA, Anflene, ANG797, Anilixin, Anmerushin, Annexin 1 peptides,annexin A5, Anodyne, Ansaid, Anspirin, Antarene, Anti BST2 antibody,Anti C5a MAb, Anti ILT7 antibody, Anti VLA1 antibody, Anti-alphal 1antibody, Anti-CD4 802-2, Anti-CD86 Monoclonal Antibody, Anti-chemokine,Anti-DC-SIGN, Anti-HMGB-1 MAb, Anti-IL-18 Mab, Anti-IL-1R MAb,Anti-IL-1R MAb, Anti-IL23 BRISTOL, Anti-inflammatory Peptides,Anti-interleukin 1Beta antibody, Anti-LIGHT antibody, Anti-LIGHTantibody, Anti-MIF Antibody, Anti-MIF Antibody, Anti-miR181a,antioxidant inflammation modulators, Antiphlamine, AntiRAGE MAb,antithrombin III, Anti-TIRC-7 MAb, Anusol-HC, Anyfen, AP105, AP1089,AP1189, AP401, AP501, apazone, APD334, Apentac, APG103, Apidone,apilimod mesylate, Apitac, Apitoxin, Apizel, APN Inhibitor,apo-Azathioprine, Apo-Dexamethasone, ApoE mimetics, ApoFasL,apo-Indomethacin, apo-mefenamic, apo-methotrexate, apo-nabumetone,Apo-Napro-NA, apo-Naproxen, aponidin, apo-Phenylbutazone, apo-Piroxicam,apo-Sulin, Apo-Tenoxicam, apo-Tiaprofenic, Apranax, apremilast,apricoxib, Aprofen, Aprose, Aproxen, APX001 antibody, APX007 antibody,APY0201, AqvoDex, AQX108, AQX1125, AQX131135, AQX140, AQX150, AQX200,AQX356, AQXMN100, AQXMN106, ARA290, Arava, Arcalyst, Arcoxia, Arechin,Arflur, ARG098, ARG301, arginine aescin, arginine deiminase (pegylated),ARGX109 antibody, ARGX110, Arheuma, Aristocort, Aristospan, Ark-AP,ARN4026, Arofen, Aroff EZ, Arolef, Arotal, Arpibru, Arpimune, ArpuShuangxin, ARQ101, Arrestin SP, Arrox, ARRY162, ARRY371797, ARRY614,ARRY872, ART621, Artamin, Arthfree, Artho Tech, Arthrexin, Arthrispray,Arthrotec, Arthrovas, Artifit, Artigo, Artin, Artinor, Artisid,Artoflex, Artren Hipergel, Artridol, Artrilase, Artrocaptin, Artrodiet,Artrofen, Artropan, Artrosil, Artrosilene, Artrotin, Artrox, Artyflam,Arzerra, AS604850, AS605858, Asacol, ASA-Grindeks, Asazipam, Aseclo,ASF1096, ASF1096, ASK8007, ASKP1240, ASLAN003, Asmo ID, Asonep, ASP015K,ASP2408, ASP2409, Aspagin, Aspeol, Aspicam, Aspirimex, aspirin, AST120,astaxanthin, AstroCort, Aszes, AT002 antibody, AT007, AT008 antibody,AT008 antibody, AT010, AT1001, atacicept, Ataspin, Atepadene, Atgam,ATG-Fresenius, Athrofen, ATIO03, atiprimod, ATL1222, ATN103, ATN192,ATR107, Atri, Atrmin, Atrosab antibody, ATX3105, AU801, auranofin,Aurobin, Auropan, Aurothio, aurotioprol, autologous adipose derivedregenerative cells, Autonec, Avandia, AVE9897, AVE9940, Avelox, Avent,AVI3378, Avloquin, AVP13546, AVP13748, AVP28225, AVX002, AxcelDiclofenac, Axcel Papain, Axen, AZ17, AZ175, Azacortid, AZA-DR,Azafrine, Azamun, Azanin, Azap, Azapin, Azapren, Azaprin, Azaram,Azasan, azathioprine, AZD0275, AZD0902, AZD2315, AZD5672, AZD6703,AZD7140, AZD8309, AZD8566, AZD9056, Azet, Azintrel, azithromycin, Az-od,Azofit, Azolid, Azoran, Azulene, Azulfidine, Azulfin, B1 antagonists,Baclonet, BAF312, BAFF Inhibitor, Bages, Baily S.P., Baleston,Balsolone, baminercept alfa, bardoxolone methyl, baricitinib, Barotase,Basecam, basiliximab, Baxmune, Baxo, BAY869766, BB2827, BCX34, BCX4208,Becfine, Beclate-C, Beclate-N, Beclolab Q, beclomethasone dipropionate,Beclorhin, Becmet-CG, Begita, Begti, belatacept, belimumab, Belosalic,Bemetson, Ben, Benevat, Benexam, Benflogin, Benisan, Benlysta, Benlysta,benorilate, Benoson, benoxaprofen, Bentol, benzydamine hydrochloride,Benzymin, Beofenac, Berafen, Berinert, Berlofen, Bertanel, Bestamine,Bestofen, Beta Nicip, Betacort, Betacorten G, Betafoam, beta-glucan,Betalar, Beta-M, Betamed, Betamesol, betamethasone, betamethasonedipropionate, betamethasone sodium, betamethasone sodium phosphate,betamethasone valerate, Betane, Betanex, Betapanthen, Betapar, Betapred,Betason, Betasonate, Betasone, Betatrinta, Betaval, Betazon, Betazone,Betesil, Betnecort, Betnesol, Betnovate, Bextra, BFPC13, BFPC18, BFPC21,BFPT6864, BG12, BG9924, BI695500, BI695501, BIA12, Big-Joint-D, BIIB023antibody, Bi-ksikam, Bingo, BioBee, Bio-Cartilage, Bio-C-Sinkki,Biodexone, Biofenac, Bioreucam, Biosone, Biosporin, BIRB796, Bitnoval,Bitvio, Bivigam, BKT140, BKTP46, BL2030, BL3030, BL4020, BL6040, BL7060,BLI1300, blisibimod, Blokium B12, Blokium Gesic, Blokium, BMS066,BMS345541, BMS470539, BMS561392, BMS566419, BMS582949, BMS587101,BMS817399, BMS936557, BMS945429, BMS-A, BN006, BN007, BNP166, Bonacort,Bonas, bone marrow stromal cell antigen 2 antibody, Bonflex, Bonifen,Boomiq, Borbit, Bosong, BRO2001, BR3-FC, Bradykinin B1 ReceptorAntagonist, Bredinin, Brexecam, Brexin, Brexodin, briakinumab, Brimani,briobacept, Bristaflam, Britten, Broben, brodalumab, Broen-C,bromelains, Bromelin, Bronax, Bropain, Brosiral, Bruace, Brufadol,Brufen, Brugel, Brukil, Brusil, BT061, BTI9, BTK kinase inhibitors,BTT1023 antibody, BTT1507, bucillamine, Bucillate, Buco Reigis,bucolome, Budenofalk, budesonide, Budex, Bufect, Bufencon, BukwangKetoprofen, Bunide, Bunofen, Busilvex, busulfan, Busulfex, Busulipo,Butartrol, Butarut B12, Butasona, Butazolidin, Butesone, Butidiona,BVX10, BXL628, BYM338, B-Zone, C1 esterase inhibitor, C243, c4462,c5997, C5aQb, c7198, c9101, C9709, c9787, CAB101, cadherin 11 antibody,caerulomycin A, CAL263, Calcort, Calmatel, CAM3001, Camelid Antibodies,Camlox, Camola, Campath, Camrox, Camtenam, canakinumab, Candida albicansantigen, Candin, cannabidiol, CAP1.1, CAP1.2, CAP2.1, CAP2.2, CAP3.1,CAP3.2, Careram, Carimune, Cariodent, Cartifix, CartiJoint, Cartilago,Cartisafe-DN, Cartishine, Cartivit, Cartril-S, Carudol, CaspaCIDe,CaspaCIDe, Casyn, CAT1004, CAT1902, CAT2200, Cataflam, Cathepsin Sinhibitor, Catlep, CB0114, CB2 agonist, CC0478765, CC10004, CC10015,CC1088, CC11050, CC13097, CC15965, CC16057, CC220, CC292, CC401, CC5048,CC509, CC7085, CC930, CCR1 Antagonist, CCR6 Inhibitor, CCR7 Antagonist,CCRL2 antagonist, CCX025, CCX354, CCX634, CD Diclofenac, CD102, CD103Antibody, CD103 Antibody, CD137 antibody, CD16 antibody, CD18 antibody,CD19 antibody, CD1d Antibody, CD20 antibody, CD200Fc, CD209 antibody,CD24, CD3 antibody, CD30 antibody, CD32A antibody, CD32B antibody, CD4antibody, CD40 ligand, CD44 antibody, CD64 antibody, CDC839, CDC998,CDIM4, CDIM9, CDK9-Inhibitor, CDP146, CDP323, CDP484, CDP6038, CDP870,CDX1135, CDX301, CE224535, Ceanel, Cebedex, Cebutid, Ceclonac, Ceex,CEL2000, Celact, Celbexx, Celcox, Celebiox, Celebrex, Celebrin, Celecox,celecoxib, Celedol, Celestone, Celevex, Celex, CELG4, Cell adhesionmolecule antagonists, CellCept, Cellmune, Celosti, Celoxib, Celprot,Celudex, cenicriviroc mesylate, cenplace1-1, CEP11004, CEP37247,CEP37248, Cephyr, Ceprofen, Certican, certolizumab pegol, Cetofenid,Cetoprofeno, cetylpyridinium chloride, CF101, CF402, CF502, CG57008,CGEN15001, CGEN15021, CGEN15051, CGEN15091, CGEN25017, CGEN25068,CGEN40, CGEN54, CGEN768, CGEN855, CGI1746, CGI560, CGI676,Cgtx-Peptides, CH1504, CH4051, CH4446, chaperonin 10, chemokine C-Cmotif ligand 2, chemokine C-C motif ligand 2 antibody, chemokine C-Cmotif ligand 5 antibody, chemokine C-C motif receptor 2 antibody,chemokine C-C motif receptor 4 antibody, chemokine C-X-C motif ligand 10antibody, chemokine C-X-C motif ligand 12 aptamer, Chemotaxis Inhibitor,Chillmetacin, chitinase 3-like 1, Chlocodemin, Chloquin, chlorhexidinegluconate, chloroquine phosphate, choline magnesium trisalicylate,chondroitin sulfate, Chondroscart, CHR3620, CHR4432, CHR5154, Chrysalin,Chuanxinlian, Chymapra, Chymotase, chymotrypsin, Chytmutrip, CI202,CI302, Cicloderm-C, Ciclopren, Cicporal, Cilamin, Cimzia, cinchophen,cinmetacin, cinnoxicam, Cinoderm, Cinolone-S, Cinryze, Cipcorlin,cipemastat, Cipol-N, Cipridanol, Cipzen, Citax F, Citogan, Citoken T,Civamide, CJ042794, CJ14877, c-Kit monoclonal antibody, cladribine,Clafen, Clanza, Claversal, clazakizumab, Clearoid, Clease, Clevegen,Clevian, Clidol, Clindac, Clinoril, Cliptol, Clobenate, Clobequad,clobetasol butyrate, clobetasol propionate, Clodol, clofarabine, Clofen,Clofenal LP, Clolar, Clonac, Clongamma, clonixin lysine, Clotasoce,Clovacort, Clovana, Cloxin, CLT001, CLT008, C-MAF Inhibitor, CMPX1023,Cnac, CNDO201, CNI1493, CNTO136, CNTO148, CNTO1959, Cobefen,CoBenCoDerm, Cobix, Cofenac, Cofenac, COG241, COL179, colchicine,Colchicum Dispert, Colchimax, Colcibra, Coledes A, Colesol, Colifoam,Colirest, collagen, type V, Comcort, complement component (3b/4b)receptor 1, Complement Component Cls Inhibitors, complement componentC3, complement factor 5a receptor antibody, complement factor 5areceptor antibody, complement factor D antibody, Condrosulf, Condrotec,Condrothin, conestat alfa, connective tissue growth factor antibody,Coolpan, Copaxone, Copiron, Cordefla, Corhydron, Cort S, Cortan,Cortate, Cort-Dome, Cortecetine, Cortef, Corteroid, Corticap, Corticas,Cortic-DS, corticotropin, Cortiderm, Cortidex, Cortiflam, Cortinet M,Cortinil, Cortipyren B, Cortiran, Cortis, Cortisolu, cortisone acetate,Cortival, Cortone acetate, Cortopin, Cortoral, Cortril, Cortypiren,Cosamine, Cosone, cosyntropin, COT Kinase Inhibitor, Cotilam, Cotrisone,Cotson, Covox, Cox B, COX-2/5-LO Inhibitors, Coxeton, Coxflam, Coxicam,Coxitor, Coxtral, Coxypar, CP195543, CP412245, CP424174, CP461,CP629933, CP690550, CP751871, CPSI2364, C-quin, CR039, CR074, CR106,CRA102, CRAC channel inhibitor, CRACM Ion Channel Inhibitor, Cratisone,CRB15, CRC4273, CRC4342, C-reactive protein 2-methoxy ethylphosphorothioate oligonucleotide, CreaVax-RA, CRH modulators,critic-aid, Crocam, Crohnsvax, Cromoglycic acid, cromolyn sodium,Cronocorteroid, Cronodicasone, CRTX803, CRx119, CRx139, CRx150, CS502,CS670, CS706, CSF1R Kinase Inhibitors, CSL324, CSL718, CSL742, CT112,CT1501R, CT200, CT2008, CT2009, CT3, CT335, CT340, CT5357, CT637, CTP05,CTP10, CT-P13, CTP17, Cuprenil, Cuprimine, Cuprindo, Cupripen, Curaquin,Cutfen, CWF0808, CWP271, CX1020, CX1030, CX1040, CX5011, Cx611, Cx621,Cx911, CXC chemokine receptor 4 antibody, CXCL13 antibodies, CXCR3antagonists, CXCR4 antagonist, Cyathus 1104 B, Cyclo-2, Cyclocort,cyclooxygenase-2 inhibitor, cyclophosphamide, Cyclorine, Cyclosporin AProdrug, Cyclosporin analogue A, cyclosporine, Cyrevia, Cyrin CLARIS,CYT007TNFQb, CYT013IL1bQb, CYT015IL17Qb, CYT020TNFQb, CYT107, CYT387,CYT99007, cytokine inhibitors, Cytopan, Cytoreg, CZC24832, D1927,D9421C, daclizumab, danazol, Danilase, Dantes, Danzen, dapsone, Dase-D,Daypro, Daypro Alta, Dayrun, Dazen, DB295, DBTP2, D-Cort, DD1, DD3,DE096, DE098, Debio0406, Debio0512, Debio0615, Debio0618, Debio1036,Decaderm, Decadrale, Decadron, Decadronal, Decalon, Decan, Decason,Decdan, Decilone, Declophen, Decopen, Decorex, Decorten, Dedema, Dedron,Deexa, Defcort, De-flam, Deflamat, Deflan, Deflanil, Deflaren, Deflaz,deflazacort, Defnac, Defnalone, Defnil, Defosalic, Defsure, Defza,Dehydrocortison, Dekort, Delagil, delcasertib, delmitide, Delphicort,Deltacorsolone, Deltacortril, Deltafluorene, Deltasolone, Deltasone,Deltastab, Deltonin, Demarin, Demisone, Denebola, denileukin diftitox,denosumab, Denzo, Depocortin, Depo-medrol, Depomethotrexate, Depopred,Deposet, Depyrin, Derinase, Dermol, Dermolar, Dermonate, Dermosone,Dersone, Desketo, desonide, desoxycorticosterone acetate, Deswon, Dexa,Dexabene, Dexacip, Dexacort, Dexacortisone, Dexacotisil, Dexadic,Dexadrin, Dexadron, Dexafar, Dexahil, Dexalab, Dexalaf, Dexalet,Dexalgen, Dexallion, Dexalocal, Dexalone, Dexa-M, Dexamecortin, Dexamed,Dexamedis, Dexameral, Dexameta, Dexamethasone, dexamethasone acetate,dexamethasone palmitate, dexamethasone phosphate, dexamethasone sodiummetasulfobenzoate, dexamethasone sodium phosphate, Dexamine,Dexapanthen, Dexa-S, Dexason, Dexatab, Dexatopic, Dexaval, Dexaven,Dexazolidin, Dexazona, Dexazone, Dexcor, Dexibu, dexibuprofen, Dexico,Dexifen, Deximune, dexketoprofen, dexketoprofen trometamol, Dexmark,Dexomet, Dexon I, Dexonalin, Dexonex, Dexony, Dexoptifen, Dexpin,Dextan-Plus, dextran sulfate, Dezacor, Dfz, diacerein, Diannexin,Diastone, Dicarol, Dicasone, Dicknol, Diclo, Diclobon, Diclobonse,Diclobonzox, Diclofast, Diclofen, diclofenac, diclofenacbeta-dimethylaminoethanol, diclofenac deanol, diclofenac diethylamine,diclofenac epolamine, diclofenac potassium, diclofenac resinate,diclofenac sodium, Diclogen AGIO, Diclogen Plus, Diclokim, Diclomed,Diclo-NA, Diclonac, Dicloramin, Dicloran, Dicloreum, Diclorism,Diclotec, Diclovit, Diclowal, Diclozem, Dico P, Dicofen, Dicoliv,Dicorsone, Dicron, Dicser, Difena, Diffutab, diflunisal, dilmapimod,Dilora, dimethyl sulfone, Dinac, D-Indomethacin, Dioxaflex Protect,Dipagesic, Dipenopen, Dipexin, Dipro AS, Diprobeta, Diprobetasone,Diproklenat, Dipromet, Dipronova, Diprosone, Diprovate, Diproxen,Disarmin, Diser, Disopain, Dispain, Dispercam, Distamine, Dizox, DLT303,DLT404, DM199, DM99, DMI9523, dnaJP1, DNX02070, DNX04042, DNX2000,DNX4000, docosanol, Docz-6, Dolamide, Dolaren, Dolchis, Dolex, Dolflam,Dolfre, Dolgit, Dolmax, Dolmina, Dolo Ketazon, Dolobest, Dolobid, Doloc,Dolocam, Dolocartigen, Dolofit, Dolokind, Dolomed, Dolonac, Dolonex,Dolotren, Dolozen, Dolquine, Dom0100, Dom0400, Dom0800, Domet, Dometon,Dominadol, Dongipap, Donica, Dontisanin, doramapimod, Dorixina Relax,Dormelox, Dorzine Plus, Doxatar, Doxtran, DP NEC, DP4577, DP50, DP6221,D-Penamine, DPIV/APN Inhibitors, DR1 Inhibitors, DR4 Inhibitors, DRA161,DRA162, Drenex, DRF4848, DRL15725, Drossadin, DSP, Duexis, Duo-Decadron,Duoflex, Duonase, DV1079, DV1179, DWJ425, DWP422, Dymol, DYN15, Dynapar,Dysmen, E5090, E6070, Easy Dayz, Ebetrexat, EBI007, ECO286, EC0565,EC0746, Ecax, Echinacea purpurea extract, EC-Naprosyn, Econac, Ecosprin300, Ecosprin 300, Ecridoxan, eculizumab, Edecam, efalizumab,Efcortesol, Effigel, Eflagen, Efridol, EGFR Antibody, EGS21, eIF5A1siRNA, Ekarzin, elafin, Eldoflam, Elidel, Eliflam, Elisone, Elmes,Elmetacin, ELND001, ELND004, elocalcitol, Elocom, elsibucol, Emanzen,Emcort, Emifen, Emifenac, emorfazone, Empynase, emricasan, Emtor,Enable, Enbrel, Enceid, EncorStat, Encortolon, Encorton, Endase,Endogesic, Endoxan, Enkorten, Ensera, Entocort, Enzylan, Epanova,Eparang, Epatec, Epicotil, epidermal growth factor receptor 2 antibody,epidermal growth factor receptor antibody, Epidixone, Epidron, Epiklin,EPPA1, epratuzumab, EquiO, Erac, Erazon, ERB041, ERB196, Erdon, EryDex,Escherichia coli enterotoxin B subunit, Escin, E-Selectin Antagonists,Esfenac, ESN603, esonarimod, Esprofen, estetrol, Estopein, EstrogenReceptor beta agonist, etanercept, etaracizumab, ETC001, ethanolpropolis extract, ETI511, etiprednol dicloacetate, Etodin, Etodine,Etodol, etodolac, Etody, etofenamate, Etol Fort, Etolac, Etopin,etoricoxib, Etorix, Etosafe, Etova, Etozox, Etura, Eucob, Eufans,eukaryotic translation initiation factor 5A oligonucleotide, Eunac,Eurocox, Eurogesic, everolimus, Evinopon, EVT401, Exaflam, EXEL9953,Exicort, Expen, Extra Feverlet, Extrapan, Extrauma, Exudase, F16, F991,Falcam, Falcol, Falzy, Farbovil, Farcomethacin, Famerate, Farnezone,Farnezone, Farotrin, fas antibody, Fastflam, FasTRACK, Fastum,Fauldmetro, FcgammaRlA antibody, FE301, Febrofen, Febrofid, felbinac,Feldene, Feldex, Feloran, Felxicam, Fenac, Fenacop, Fenadol, Fenaflan,Fenamic, Fenaren, Fenaton, Fenbid, fenbufen, Fengshi Gutong, Fenicort,Fenopine, fenoprofen calcium, Fenopron, Fenris, Fensupp, Fenxicam,fepradinol, Ferovisc, Feverlet, fezakinumab, FG3019, FHT401, FHTCT4,FID114657, figitumumab, Filexi, filgrastim, Fillase, Final, Findoxin,fingolimod hydrochloride, firategrast, Firdapse, Fisiodar, Fivasa,FK778, Flacoxto, Fladalgin, Flagon, Flamar, Flamcid, Flamfort, Flamide,Flaminase, Flamirex Gesic, Flanid, Flanzen, Flaren, Flaren, Flash Act,Flavonoid Anti-inflammatory Molecule, Flebogamma DIF, Flenac, Flex,Flexafen 400, Flexi, Flexidol, Flexium, Flexon, Flexono, Flogene,Flogiatrin B12, Flogomin, Flogoral, Flogosan, Flogoter, Flo-Pred,Flosteron, Flotrip Forte, Flt3 inhibitors, fluasterone, Flucam,Flucinar, fludrocortisone acetate, flufenamate aluminum, flumethasone,Flumidon, flunixin, fluocinolone, fluocinolone acetonide, fluocinonide,fluocortolone, Fluonid, fluorometholone, Flur, flurbiprofen, Fluribec,Flurometholone, Flutal, fluticasone, fluticasone propionate, Flutizone,Fluzone, FM101 antibody, fms-related tyrosine kinase 1 antibody,Folitrax, fontolizumab, formic acid, Fortecortin, Fospeg, fostamatinibdisodium, FP1069, FP13XX, FPA008, FPA031, FPT025, FR104, FR167653,Framebin, Frime, Froben, Frolix, FROUNT Inhibitors, Fubifen PAP, Fucoleibuprofen, Fulamotol, Fulpen, Fungifin, Furotalgin, fusidate sodium,FX002, FX141L, FX201, FX300, FX87L, Galectin modulators, galliummaltolate, Gamimune N, Gammagard, Gamma-I.V., GammaQuin, Gamma-Venin,Gamunex, Garzen, Gaspirin, Gattex, GBR500, GBR500 antibody, GBT009,G-CSF, GED0301, GED0414, Gefenec, Gelofen, Genepril, Gengraf, Genimune,Geniquin, Genotropin, Genz29155, Gerbin, Gerbin, gevokizumab,GF01564600, Gilenia, Gilenya, givinostat, GL0050, GL2045, glatirameracetate, Globulin, Glortho Forte, Glovalox, Glovenin-I, GLPG0259,GLPG0555, GLPG0634, GLPG0778, GLPG0974, Gluco, Glucocerin, glucosamine,glucosamine hydrochloride, glucosamine sulfate, Glucotin, Gludex,Glutilage, GLY079, GLY145, Glycanic, Glycefort up, Glygesic, Glysopep,GMCSF Antibody, GMI1010, GMI1011, GMI1043, GMR321, GN4001, Goanna Salve,Goflex, gold sodium thiomalate, golimumab, GP2013, GPCR modulator, GPR15Antagonist, GPR183 antagonist, GPR32 antagonist, GPR83 antagonist,G-protein Coupled Receptor Antagonists, Graceptor, Graftac, granulocytecolony-stimulating factor antibody, granulocyte-macrophagecolony-stimulating factor antibody, Gravx, GRC4039, Grelyse, GS101,GS9973, GSC100, GSK1605786, GSK1827771, GSK2136525, GSK2941266,GSK315234, GSK681323, GT146, GT442, Gucixiaotong, Gufisera, Gupisone,gusperimus hydrochloride, GW274150, GW3333, GW406381, GW856553, GWB78,GXP04, Gynestrel, Haloart, halopredone acetate, Haloxin, HANALL, HanallSoludacortin, Havisco, Hawon Bucillamin, HB802, HC31496, HCQ 200, HD104,HD203, HD205, HDAC inhibitor, HE2500, HE3177, HE3413, Hecoria,Hectomitacin, Hefasolon, Helen, Helenil, HemaMax, Hematom, hematopoieticstem cells, Hematrol, Hemner, Hemril, heparinoid, Heptax, HER2 Antibody,Herponil, hESC Derived Dendritic Cells, hESC Derived Hematopoietic stemcells, Hespercorbin, Hexacorton, Hexadrol, hexetidine, Hexoderm,Hexoderm Salic, HF0220, HF1020, HFT-401, hG-CSFR ED Fc, Hiberna, highmobility group box 1 antibody, Hiloneed, Hinocam, hirudin, Hirudoid,Hison, Histamine H4 Receptor Antagonist, Hitenercept, Hizentra, HL036,HL161, HMPL001, HMPL004, HMPL004, HMPL011, HMPL342, HMPL692, honey beevenom, Hongqiang, Hotemin, HPH116, HTI101, HuCAL Antibody, Human adiposemesenchymal stem cells, anti-MHC class II monoclonal antibody, HumanImmunoglobulin, Human Placenta Tissue Hydrolysate, HuMaxCD4, HuMax-TAC,Humetone, Humicade, Humira, Huons Betamethasone sodium phosphate, Huonsdexamethasone sodium phosphate, Huons Piroxicam, Huons Talniflumate,Hurofen, Huruma, Huvap, HuZAF, HX02, Hyalogel, hyaluronate sodium,hyaluronic acid, hyaluronidase, Hyaron, Hycocin, Hycort, Hy-Cortisone,hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate,hydrocortisone hemisuccinate, hydrocortisone sodium phosphate,hydrocortisone sodium succinate, Hydrocortistab, Hydrocortone, Hydrolin,Hydroquine, Hydro-Rx, Hydrosone HIKMA, hydroxychloroquine,hydroxychloroquine sulfate, Hylase Dessau, HyMEX, Hypen, HyQ, Hysonate,HZN602, I.M.75, IAP Inhibitors, Ibalgin, Ibalgin, Ibex, ibrutinib,IBsolvMIR, Ibu, Ibucon, Ibudolor, Ibufen, Ibuflam, Ibuflex, Ibugesic,Ibu-Hepa, Ibukim, Ibumal, Ibunal, Ibupental, Ibupril, Ibuprof,ibuprofen, Ibuscent, Ibusoft, Ibusuki Penjeong, Ibususpen, Ibutard,Ibutop, Ibutop, Ibutrex, IC487892, ichthammol, ICRAC Blocker, IDEC131,IDECCE9.1, Ides, Idicin, Idizone, IDN6556, Idomethine, IDR1, Idyl SR,Ifen, iguratimod, IK6002, IKK-beta inhibitor, IL17 Antagonist, IL-17Inhibitor, IL-17RC, IL18, IL1Hyl, IL1R1, IL-23 Adnectin, IL23 Inhibitor,IL23 Receptor Antagonist, IL-31 mAb, IL-6 Inhibitor, IL6Qb, Ilacox,Ilaris, ilodecakin, ILV094, ILV095, Imaxetil, IMD0560, IMD2560, ImeselPlus, Iminoral, Immodin, IMMU103, IMMU106, Immucept, Immufine, ImmunexSyrup, immunoglobulin, immunoglobulin G, Immunoprin, ImmunoRel, Immurin,IMO8400, IMP731 antibody, Implanta, Imunocell, Imuran, Imurek, Imusafe,Imusporin, Imutrex, IN0701, Inal, INCB039110, INCB18424, INCB28050,INCB3284, INCB3344, Indexon, Indic, Indo, Indo-A, Indobid, Indo-Bros,Indocaf, Indocarsil, Indocid, Indocin, Indomehotpas, Indomen, Indomet,Indometacin, indomethacin, Indomethasone, Indometin, Indomin, Indopal,Indoron, Indotroxin, INDUS830, INDUS83030, Infladase, Inflamac,Inflammasome inhibitor, Inflavis, Inflaxen, Inflectra, infliximab,Ingalipt, Inicox dp, Inmecin, Inmunoartro, Innamit, InnoD06006, IN07997,Inocin, Inoten, Inovan, Inpra, Inside Pap, Insider-P, Instacyl,Instracool, Intafenac, Intaflam, Inteban, Inteban Spansule, integrin,alpha 1 antibody, integrin, alpha 2 antibody, Intenurse, interferonalfa, interferon beta-1a, interferon gamma, interferon gamma antibody,Interking, interleukin 1 Hyl, interleukin 1 antibody, interleukin 1receptor antibody, interleukin 1, beta antibody, interleukin 10,interleukin 10 antibody, interleukin 12, interleukin 12 antibody,interleukin 13 antibody, interleukin 15 antibody, interleukin 17antibody, interleukin 17 receptor C, interleukin 18, interleukin 18binding protein, interleukin 18 antibody, interleukin 2 receptor, alphaantibody, interleukin 20 antibody, Interleukin 21 mAb, interleukin 23aptamer, interleukin 31 antibody, interleukin 34, Interleukin 6Inhibitor, interleukin 6 antibody, interleukin 6 receptor antibody,interleukin 7, interleukin 7 receptor antibody, interleukin 8,interleukin 8 antibody, interleukin-18 antibody, Intidrol, Intradex,Intragam P, Intragesic, Intraglobin F, Intratect, Inzel, lomab B,IOR-T3, IP751, IPH2201, IPH2301, IPH24, IPH33, IPI145, Ipocort,IPP201007, I-Profen, Iprox, Ipson, Iputon, IRAK4 Inhibitor, Iremod,Irtonpyson, IRX3, IRX5183, ISA247, ISIS104838, ISIS2302, ISISCRPRx,Ismafron, IsoQC inhibitor, Isox, ITF2357, Iveegam EN, Ivepred, IVIG-SN,IWO01, Izilox, J607Y, J775Y, JAK Inhibitor, JAK3 inhibitor, JAK3 kinaseinhibitor, JI3292, JI4135, Jinan Lida, JNJ10329670, JNJ18003414,JNJ26528398, JNJ27390467, JNJ28838017, JNJ31001958, JNJ38518168,JNJ39758979, JNJ40346527, JNJ7777120, JNT-Plus, Joflam, JointGlucosamin, Jointec, Jointstem, Joinup, JPE1375, JSM10292, JSM7717,JSM8757, JTE051, JTE052, JTE522, JTE607, Jusgo, K412, K832, Kaflam,KAHR101, KAHR102, KAI9803, Kalymin, Kam Predsol, Kameton, KANAb071,Kappaproct, KAR2581, KAR3000, KAR3166, KAR4000, KAR4139, KAR4141, KB002,KB003, KD7332, KE298, keliximab, Kemanat, Kemrox, Kenacort, Kenalog,Kenaxir, Kenketsu Venoglobulin-IH, Keplat, Ketalgipan, Keto Pine, Keto,Ketobos, Ketofan, Ketofen, Ketolgan, Ketonal, Ketoplus Kata Plasma,ketoprofen, Ketores, Ketorin, ketorolac, ketorolac tromethamine,Ketoselect, Ketotop, Ketovail, Ketricin, Ketroc, Ketum, Keyi, Keyven,KF24345, K-Fenac, K-Fenak, K-Gesic, Kifadene, Kilcort, Kildrol, KIM127,Kimotab, Kinase Inhibitor 4SC, Kinase N, Kincort, Kindorase, Kineret,Kineto, Kitadol, Kitex, Kitolac, KLK1 Inhibitor, Klofen-L, Klotaren,KLS-40or, KLS-40ra, KM277, Knavon, Kodolo orabase, Kohakusanin, Koide,Koidexa, Kolbet, Konac, Kondro, Kondromin, Konshien, Kontab, Kordexa,Kosa, Kotase, KPE06001, KRP107, KRP203, KRX211, KRX252, KSB302, K-Sep,Kv 1.3 Blocker, Kv1.3 4SC, Kv1.3 inhibitor, KVK702, Kynol, L156602,Labizone, Labohydro, Labopen, Lacoxa, Lamin, Lamit, Lanfetil,laquinimod, larazotide acetate, LAS186323, LAS187247, LAS41002,Laticort, LBEC0101, LCP3301, LCP-Siro, LCP-Tacro, LCsA, LDP392, Leap-S,Ledercort, Lederfen, Lederlon, Lederspan, Lefenine, leflunomide, Leflux,Lefno, Lefra, Leftose, Lefumide, Lefunodin, Lefva, lenalidomide,lenercept, LentiRA, LE015520, Leodase, Leukine, Leukocytefunction-associated antigen-1 antagonist, leukocyte immunoglobulin-likereceptor, subfamily A, member 4 antibody, Leukothera, leuprolideacetate, levalbuterol, levomenthol, LFA-1 Antagonist, LFA451, LFA703,LFA878, LG106, LG267 Inhibitors, LG688 Inhibitors, LGD5552, Li Life,LidaMantle, Lidex, lidocaine, lidocaine hydrochloride, Lignocainehydrochloride, LIM0723, LIM5310, Limethason, Limus, Limustin, Lindac,Linfonex, Linola acute, Lipcy, lisofylline, Listran, Liver X Receptormodulator, Lizak, LP1207, LJP920, Lobafen, Lobu, Locafluo, Localyn,Locaseptil-Neo, Locpren, Lodine, Lodotra, Lofedic, Loflam, Lofnac,Lolcam, Lonac, lonazolac calcium, Loprofen, Loracort, Lorcam,Lorfenamin, Lorinden Lotio, Lorncrat, lornoxicam, Lorox, losmapimod,loteprednol etabonate, Loteprednol, Lotirac, Low Molecular GanodermaLucidum Polysaccharide, Loxafen, Loxfenine, Loxicam, Loxofen, Loxonal,Loxonin, loxoprofen sodium, Loxoron, LP183A1, LP183A2, LP204A1,LPCN1019, LT1942, LT1964, LTNS101, LTNS103, LTNS106, LTNS108, LTS1115,LTZMP001, Lubor, lumiracoxib, Lumitect, LX2311, LX2931, LX2932,LY2127399, LY2189102, LY2439821, LY294002, LY3009104, LY309887,LY333013, lymphocyte activation gene 3 antibody, Lymphoglobuline, Lyser,lysine aspirin, Lysobact, Lysoflam, Lysozyme hydrochloride, M3000, M834,M923, mAb hG-CSF, MABP1, macrophage migration inhibitory factorantibody, Maitongna, Majamil prolongatum, major histocompatibilitycomplex class II DR antibody, major histocompatibility complex class IIantibody, Malidens, Malival, mannan-binding lectin, mannan-bindinglectin-associated serine protease-2 antibody, MapKap Kinase 2 Inhibitor,maraviroc, Marlex, masitinib, Maso, MASP2 antibody, MAT304, MatrixMetalloprotease Inhibitor, mavrilimumab, Maxiflam, Maxilase, Maximus,Maxisona, Maxius, Maxpro, Maxrel, Maxsulid, Maxyl2, Maxy30, MAXY4,Maxy735, Maxy740, Mayfenamic, MB11040, MBPY003b, MCAF5352A, McCam,McRofy, MCS18, MD707, MDAM, MDcort, MDR06155, MDT012, Mebicam, Mebuton,meclofenamate sodium, Meclophen, Mecox, Medacomb, Medafen, Medamol,Medesone, MEDI2070, MEDI5117, MEDI541, MEDI552, MEDI571, Medicox,Medifen, Medisolu, Medixon, Mednisol, Medrol, Medrolon,medroxyprogesterone acetate, Mefalgin, mefenamic acid, Mefenix,Mefentan, Meflen, Mefnetra forte, Meftagesic-DT, Meftal, MegakaryocyteGrowth and Development Factor, Megaspas, Megaster, megestrol acetate,Meite, Meksun, Melbrex, Melcam, Melcam, Melflam, Melic, Melica, Melix,Melocam, Melocox, Mel-One, Meloprol, Melosteral, Melox, Meloxan,Meloxcam, Meloxic, Meloxicam, Meloxifen, Meloxin, Meloxiv, Melpred,Melpros, Melurjin, Menamin, Menisone, Menthomketo, Menthoneurin,Mentocin, Mepa, Mepharen, meprednisone, Mepresso, Mepsolone,mercaptopurine, Mervan, Mesadoron, mesalamine, Mesasal, Mesatec,Mesenchymal Precursor Cells, mesenchymal stem cell, Mesipol, Mesren,Mesulan, Mesulid, Metacin, Metadaxan, Metaflex, Metalcaptase,metalloenzyme inhibitors, Metapred, Metax, Metaz, Meted, Metedic,Methacin, Methaderm, Methasone, Methotrax, methotrexate, methotrexatesodium, Methpred, Methyl prednisolone acetate, methyl salicylate, methylsulphonyl methane, Methylon, Methylpred, methylprednisolone,methylprednisolone acetate, methylprednisolone sodium succinate,methylprednisolone succinate, Methylprednisolone, Methysol, Metindol,Metoart, Metoject, Metolate, Metoral, Metosyn, Metotab, Metracin,Metrex, metronidazole, Metypred, Mevamox, Mevedal, Mevilox, Mevin SR,Mexilal, Mexpharm, Mext, Mextran, MF280, M-FasL, MHC class II beta chainpeptide, Micar, Miclofen, Miclofenac, Micofenolato Mofetil, Micosone,Microdase, microRNA 181a-2 oligonucleotide, MIF Inhibitors, MIFQb,MIKA-Ketoprofen, Mikametan, milodistim, Miltax, Minafen, Minalfen,Minalfene, Minesulin, Minocort, Mioflex, Miolox, Miprofen, Miridacin,Mirloks, Misoclo, Misofenac, MISTB03, MISTB04, Mitilor, mizoribine,MK0359, MK0812, MK0873, MK2 Inhibitors, MK50, MK8457, MK8808, MKC204,MLN0002, MLN0415, MLN1202, MLN273, MLN3126, MLN3701, MLN3897, MLNM002,MM093, MM7XX, MN8001, Mobic, Mobicam, Mobicox, Mobifen Plus, Mobilat,Mobitil, Mocox, Modigraf, Modrasone, Modulin, Mofecept, Mofetyl,mofezolac sodium, Mofilet, Molace, molgramostim, Molslide, Momekin,Momen Gele, Moment 100, Momesone, Momesun, Mometamed, mometasone,mometasone furoate, Monimate, monosodium alpha-luminol, Mopik, MOR103,MOR104, MOR105, MOR208 antibody, MORAb022, Moricam, morniflumate,Mosuolit, Motoral, Movaxin, Mover, Movex, Movix, Movoxicam, Mox Forte,Moxen, moxifloxacin hydrochloride, Mozobil, MP, MP0210, MP0270, MP1000,MP1031, MP196, MP435, MPA, mPGES-1 inhibitor, MPSS, MRX7EAT, MSL, MT203,MT204, mTOR Inhibitor, MTRX1011A, Mucolase, Multicort, MultiStem,muramidase, muramidase, muramidase hydrochloride, muromonab-CD3, Muslax,Muspinil, Mutaze, Muvera, MX68, Mycept, Mycocell, Mycocept,Mycofenolatmofetil Actavis, Mycofet, Mycofit, Mycolate, Mycoldosa,Mycomun, Myconol, mycophenolate mofetil, mycophenolate sodium,mycophenolic acid, Mycotil, myeloid progenitor cells, Myfenax, Myfetil,Myfortic, Mygraft, Myochrysine, Myocrisin, Myprodol, Mysone,nab-Cyclosporine, Nabentac, nabiximols, Nabton, Nabuco, Nabucox,Nabuflam, Nabumet, nabumetone, Nabuton, Nac Plus, Nacta, Nacton, Nadium,Naklofen SR, NAL1207, NAL1216, NAL1219, NAL1268, NAL8202, Nalfon,Nalgesin S, namilumab, Namsafe, nandrolone, Nanocort, Nanogam, NanosomalTacrolimus, Napageln, Napilac, Naprelan, Napro, Naprodil, Napronax,Napropal, Naproson, Naprosyn, Naproval, Naprox, naproxen, naproxensodium, Naproxin, Naprozen, Narbon, Narexsin, Naril, Nasida,natalizumab, Naxdom, Naxen, Naxin, Nazovel, NC2300, ND07, NDC01352,Nebumetone, NecLipGCSF, Necsulide, Necsunim, Nelsid-S, Neo Clobenate,Neo Swiflox FC, Neocoflan, Neo-Drol, Neo-Eblimon, Neo-Hydro, Neoplanta,Neoporine, Neopreol, Neoprox, Neoral, Neotrexate, Neozen, Nepra,Nestacort, Neumega, Neupogen, Neuprex, Neurofenac, Neurogesic, Neurolab,Neuroteradol, Neuroxicam, Neutalin, neutrazumab, Neuzym, New Panazox,Newfenstop, NewGam, Newmafen, Newmatal, Newsicam, NEX1285, sFcRIIB,Nextomab, NF-kappaB Inhibitor, NF-kB inhibitor, NGD20001, NHP554B,NHP554P, NI0101 antibody, NI0401, NI0501 antibody, NI0701, NI071, NI1201antibody, NI1401, Nicip, Niconas, Nicool, NiCord, Nicox, Niflumate,Nigaz, Nikam, Nilitis, Nimace, Nimaid, Nimark-P, Nimaz, Nimcet Juicy,Nime, Nimed, Nimepast, nimesulide, Nimesulix, Nimesulon, Nimica Plus,Nimkul, Nimlin, Nimnat, Nimodol, Nimpidase, Nimsaid-S, Nimser, Nimsy-SP,Nimupep, Nimusol, Nimutal, Nimuwin, Nimvon-S, Nincort, Niofen, Nipan,Nipent, Nise, Nisolone, Nisopred, Nisoprex, Nisulid, nitazoxanide,Nitcon, nitric oxide, Nizhvisal B, Nizon, NL, NMR1947, NN8209, NN8210,NN8226, NN8555, NN8765, NN8828, NNC014100000100, NNC051869, Noak,Nodevex, Nodia, Nofenac, Noflagma, Noflam, Noflamen, Noflux,Non-antibacterial Tetracyclines, Nonpiron, Nopain, Normferon, Notpel,Notritis, Novacort, Novagent, Novarin, Novigesic, NOXA12, NOXD19, Noxen,Noxon, NPI1302a-3, NPI1342, NPI1387, NPI1390, NPRCS1, NPRCS2, NPRCS3,NPRCS4, NPRCS5, NPRCS6, NPS3, NPS4, nPT-ery, NU3450, nuclear factorNF-kappa-B p65 subunit oligonucleotide, Nucort, Nulojix, Numed-Plus,Nurokind Ortho, Nusone-H, Nutrikemia, Nuvion, NVO7alpha, NX001,Nyclobate, Nyox, Nysa, Obarcort, 00002417, 0C2286, ocaratuzumab,OCTSG815, Oedemase, Oedemase-D, ofatumumab, Ofgyl-O, Ofvista, OHR118,OKi, Okifen, Oksamen, Olai, olokizumab, Omeprose E, Omnacortil, Omneed,Omniclor, Omnigel, Omniwel, onercept, 0N04057, ONS1210, ONS1220, OntacPlus, Ontak, ONX0914, OPC6535, opebacan, OPN101, OPN201, OPN302, OPN305,OPN401, oprelvekin, OPT66, Optifer, Optiflur, OptiMIRA, Orabase Hca,Oradexon, Oraflex, OralFenac, Oralog, Oralpred, Ora-sed, Orasone, orBec,Orbone forte, Orcl, ORE10002, ORE10002, Orencia, Org214007, Org217993,Org219517, Org223119, Org37663, Org39141, Org48762, Org48775, Orgadrone,Ormoxen, Orofen Plus, Oromylase Biogaran, Orthal Forte, Ortho Flex,Orthoclone OKT3, Orthofen, Orthoflam, Orthogesic, Orthoglu, Ortho-II,Orthomac, Ortho-Plus, Ortinims, Ortofen, Orudis, Oruvail, OS2, Oscart,Osmetone, Ospain, Ossilife, Ostelox, Osteluc, Osteocerin, osteopontin,Osteral, otelixizumab, Otipax, Ou Ning, OvaSave, OX40 Ligand Antibody,Oxa, Oxagesic CB, Oxalgin DP, oxaprozin, OXCQ, Oxeno, Oxib MD, Oxibut,Oxicam, Oxiklorin, Oximal, Oxynal, oxyphenbutazone, Oxyphenbutazone,ozoralizumab, P13 peptide, P1639, P21, P2X7 Antagonists, p38 AlphaInhibitor, p38 Antagonist, p38 MAP kinase inhibitor, p38alpha MAP KinaseInhibitor, P7 peptide, P7170, P979, PA401, PA517, Pabi-dexamethasone,PAC, PAC10649, paclitaxel, Painoxam, Paldon, Palima, pamapimod,Pamatase, Panafcort, Panafcortelone, Panewin, PanGraf, Panimun Bioral,Panmesone, Panodin SR, Panslay, Panzem, Panzem NCD, PAP1, papain,Papirzin, Pappen K Pap, Paptinim-D, paquinimod, PAR2 Antagonist,Paracetamol, Paradic, Parafen TAJ, Paramidin, Paranac, Parapar, Parci,parecoxib, Parixam, Parry-S, Partaject Busulfan, pateclizumab, Paxceed,PBI0032, PBI1101, PBI1308, PBI1393, PBI1607, PBI1737, PBI2856, PBI4419,PBI4419, P-Cam, PCI31523, PCI32765, PCI34051, PCI45261, PCI45292,PCI45308, PD360324, PD360324, PDA001, PDE4 inhibitor, PDE-IV Inhibitor,PDL241 antibody, PDL252, Pediapred, Pefree, pegacaristim, Peganix,Peg-Interleukin 12, pegsunercept, Pegsunercept, PEGylated argininedeiminase, peldesine, pelubiprofen, Penacle, penicillamine, Penostop,Pentalgin, Pentasa, Pentaud, pentostatin, Peon, Pepdase, Pepser,Peptirase, Pepzen, Pepzol, Percutalgine, Periochip, PeroxisomeProliferator Activated Receptor gamma modulators, Petizene, PF00344600,PF04171327, PF04236921, PF04308515, PF05230905, PF05280586, PF251802,PF3475952, PF3491390, PF3644022, PF4629991, PF4856880, PF5212367,PF5230896, PF547659, PF755616, PF9184, PG27, PG562, PG760564, PG8395,PGE3935199, PGE527667, PHS, PH797804, PHA408, Pharmaniaga Mefenamicacid, Pharmaniaga Meloxicam, Pheldin, Phenocept, phenylbutazone, PHY702,PI3K delta inhibitor, PI3K Gamma/Delta Inhibitor, PI3K Inhibitor,Picalm, pidotimod, piketoprofen, Pilelife, Pilopil, Pilovate,pimecrolimus, Pipethanen, Piractam, Pirexyl, Pirobet, Piroc, Pirocam,Pirofel, Pirogel, Piromed, Pirosol, Pirox, Piroxen, Piroxicam, piroxicambetadex, Piroxifar, Piroxil, Piroxim, Pixim, Pixykine, PKC ThetaInhibitor, PL3100, PL5100 Diclofenac, Placenta Polypeptide, Plaquenil,plerixafor, Plocfen, PLR14, PLR18, Plutin, PLX3397, PLX5622, PLX647,PLX-BMT, pms-Diclofenac, pms-Ibuprofen, pms-Leflunomide, pms-Meloxicam,pms-Piroxicam, pms-Prednisolone, pms-Sulfasalazine, pms-Tiaprofenic,PMX53, PN0615, PN100, PN951, podofilox, POL6326, Polcortolon, Polyderm,Polygam S/D, Polyphlogin, Poncif, Ponstan, Ponstil Forte, Porine-ANeoral, Potaba, potassium aminobenzoate, Potencort, Povidone, povidoneiodine, pralnacasan, Prandin, Prebel, Precodil, Precortisyl Forte,Precortyl, Predfoam, Predicort, Predicorten, Predilab, Predilone,Predmetil, Predmix, Predna, Prednesol, Predni, prednicarbate,Prednicort, Prednidib, Prednifarma, Prednilasca, prednisolone,prednisolone acetate, prednisolone sodium phosphate, prednisolone sodiumsuccinate, prednisolone sodium succinate, prednisone, prednisoneacetate, Prednitop, Prednol-L, Prednox, Predone, Predonema, Predsol,Predsolone, Predsone, Predval, Preflam, Prelon, Prenaxol, Prenolone,Preservex, Preservin, Presol, Preson, Prexige, Priliximab, Primacort,Primmuno, Primofenac, prinaberel, Privigen, Prixam, Probuxil, Procarne,Prochymal, Procider-EF, Proctocir, Prodase, Prodel B, Prodent, ProdentVerde, Proepa, Profecom, Profenac L, Profenid, Profenol, Proflam,Proflex, Progesic Z, proglumetacin, proglumetacin maleate, Prograf,Prolase, Prolixan, promethazine hydrochloride, Promostem, Promune,PronaB, pronase, Pronat, Prongs, Pronison, Prontoflam, Propaderm-L,Propodezas, Propolisol, Proponol, propyl nicotinate, Prostaloc,Prostapol, Protacin, Protase, Protease Inhibitors, Protectan, ProteinaseActivated Receptor 2 Inhibitor, Protofen, Protrin, Proxalyoc, Proxidol,Proxigel, Proxil, Proxym, Prozym, PRT062070, PRT2607, PRTX100, PRTX200,PRX106, PRX167700, Prysolone, PS031291, PS375179, PS386113, PS540446,PS608504, PS826957, PS873266, Psorid, PT, PT17, PTL101, P-TransferFactor peptides, PTX3, Pulminiq, Pulsonid, Purazen, Pursin, PVS40200,PX101, PX106491, PX114, PXS2000, PXS2076, PYM60001, Pyralvex, Pyranim,pyrazinobutazone, Pyrenol, Pyricam, Pyrodex, Pyroxi-Kid, QAX576,Qianbobiyan, QPI1002, QR440, qT3, Quiacort, Quidofil, R107s, R125224,R1295, R132811, R1487, R1503, R1524, R1628, R333, R348, R548, R7277,R788, rabeximod, Radix Isatidis, Radofen, Raipeck, Rambazole, Randazima,Rapacan, Rapamune, Raptiva, Ravax, Rayos, RDEA119, RDEA436, RDP58,Reactine, Rebif, REC200, Recartix-DN, receptor for advanced glycationend products antibody, Reclast, Reclofen, recombinant HSA-TIMP-2,recombinant human alkaline Phosphatase, recombinant Interferon Gamma,Recominant human alkaline phosphatase, Reconil, Rectagel HC, Recticin,Recto Menaderm, Rectos, Redipred, Redolet, Refastin, Regenica, REGN88,Relafen, Relaxib, Relev, Relex, Relifen, Relifex, Relitch, Rematof,remestemce1-1, Remesulidum, Remicade, Remsima, Remsima, Remsima,ReN1869, Renacept, Renfor, Renodapt, Renodapt-S, Renta, Reosan,Repare-AR, Reparilexin, reparixin, Repertaxin, Repisprin, Resochin,Resol, resolvin E1, Resurgil, Re-tin-colloid, Retoz, Reumacap, Reumacon,Reumadolor, Reumador, Reumanisal, Reumazin, Reumel, Reumotec, Reuquinol,revamilast, Revascor, Reviroc, Revlimid, Revmoksikam, Rewalk, Rexalgan,RG2077, RG3421, RG4934 antibody, RG7416, RG7624, Rheila, Rheoma,Rheprox, Rheudenolone, Rheufen, Rheugesic, Rheumacid, Rheumacort,Rheumatrex, Rheumesser, Rheumid, Rheumon, Rheumox, Rheuoxib, Rhewlin,Rhucin, RhuDex, Rhulef, Ribox, Ribunal, Ridaura, rifaximin, rilonacept,rimacalib, Rimase, Rimate, Rimatil, Rimesid, risedronate sodium,Ritamine, Rito, Rittman, rituximab, RNS60, R01138452, Ro313948,R03244794, R05310074, Rob803, Rocamix, Rocas, Rofeb, rofecoxib, Rofee,Rofewal, Roficip Plus, Rojepen, Rokam, Rolodiquim, Romacox Fort,Romatim, romazarit, Ronaben, ronacaleret, Ronoxcin, ROR Gamma TAntagonist, ROR gamma t inverse agonists, Rosecin, rosiglitazone,Rosmarinic acid, Rotan, Rotec, Rothacin, Roxam, Roxib, Roxicam, Roxopro,Roxygin DT, RP54745, RPI78, RPI78M, RPI78MN, RPIMN, RQ00000007,RQ00000008, RTA402, R-Tyflam, Rubicalm, Rubifen, Ruma pap, Rumalef,Rumidol, Rumifen, Runomex, rusalatide acetate, ruxolitinib, RWJ445380,RX10001, Rycloser MR, Rydol, SW Receptor Agonists, SP ReceptorModulators, S1P1 Agonist, S1P1 receptor agonist, 52474, 53013, SA237,SA6541, Saaz, S-adenosyl-L-methionine-sulfate-p-toluene sulfonate, Sala,Salazidin, Salazine, Salazopyrin, Salcon, Salicam, salsalate, Sameron,SAN300, Sanaven, Sandimmun, Sandoglobulin, Sanexon, SangCya, SAR153191,SAR302503, SAR479746, Sarapep, sargramostim, Sativex, Savantac, Save,Saxizon, Sazo, SB1578, SB210396, SB217969, SB242235, SB273005, SB281832,SB683698, SB751689, SBI087, SC080036, SC12267, SC409, Scaflam, SCDketoprofen, SCI0323, SCI0469, SD-15, SD281, SDP051 antibody, Sd-rxRNA,secukinumab, Sedase, Sedilax, Sefdene, Seizyme, SEL113, Seladin,Selecox, selectin P ligand antibody, Glucocorticoid Receptor Agonist,Selectofen, Selektine, SelK1 antibody, Seloxx, Selspot, Selzen,Selzenta, Selzentry, semapimod, semapimod hydrochloride, semparatide,Semparatide, Senafen, Sendipen, Senterlic, SEP119249, Sepdase,Septirose, Seractil, Serafen-P, Serase, Seratid D, Seratiopeptidase,Serato-M, Seratoma Forte, Serazyme, Serezon, Sero, Serodase, Serpicam,Serra, serrapeptase, Serratin, Serratiopeptidase, Serrazyme, Servisone,Seven E P, SGI1252, SGN30, SGN70, SGX203, shark cartilage extract,Sheril, Shield, Shifazen, Shifazen-Fort, Shincort, Shincort, Shiosol,ShK186, Shuanghuangxiaoyan, 51615, 51636, Sigmasporin, Sigmasporin,SIM916, Simpone, Simulect, Sinacort, Sinalgia, Sinapol, Sinatrol,Sinsia, siponimod, Sirolim, sirolimus, Siropan, Sirota, Sirova,sirukumab, Sistal Forte, SKF105685, SKF105809, SKF106615, SKF86002,Skinalar, Skynim, Skytrip, SLAM family member 7 antibody, Slo-indo,SM101, SM201 antibody, SM401, SMAD family member 7 oligonucleotide,SMART Anti-IL-12 Antibody, SMP114, SN0030908, SN0070131, sodiumaurothiomalate, sodium chondroitin sulfate, sodium deoxyribonucleotide,sodium gualenate, sodium naproxen, sodium salicylate, Sodixen, Sofeo,Soleton, Solhidrol, Solicam, Soliky, Soliris, Sol-Melcort, Solomet,Solondo, Solone, Solu-Cort, Solu-Cortef, Solu-Decortin H, Solufen,Solu-Ket, Solumark, Solu-Medrol, Solupred, Somalgen, somatropin, Sonap,Sone, sonepcizumab, Sonexa, Sonim, Sonim P, Soonil, Soral, Sorenil,sotrastaurin acetate, SP-10, SP600125, Spanidin, SP-Cortil, SPD550,Spedace, sperm adhesion molecule 1, Spictol, spleen tyrosine kinaseoligonucleotide, Sporin, S-prin, SPWF1501, SQ641, SQ922, SR318B, SR9025,SRT2104, SSR150106, SSR180575, SSSO7 antibody, ST1959, STA5326, stabilin1 antibody, Stacort, Stalogesic, stanozolol, Staren, Starmelox, StedexIND-SWIFT, Stelara, Stemin, Stenirol, Sterapred, Steriderm S, Steno,Sterisone, Steron, stichodactyla helianthus peptide, Stickzenol A,Stiefcortil, Stimulan, STNM01, Store Operated Calcium Channel (SOCC)Modulator, STP432, STP900, Stratasin, Stridimmune, Strigraf, SU Medrol,Subreum, Subuton, Succicort, Succimed, Sulan, Sulcolon, SulfasalazinHeyl, Sulfasalazin, sulfasalazine, Sulfovit, Sulidac, Sulide, sulindac,Sulindex, Sulinton, Sulphafine, Sumilu, SUN597, Suprafen, Supretic,Supsidine, Surgam, Surgamine, Surugamu, Suspen, Suton, Suvenyl, Suwei,SW Dexasone, Syk Family Kinase Inhibitor, Syn1002, Synacran, Synacthen,Synalar C, Synalar, Synavive, Synercort, Sypresta, T cellcytokine-inducing surface molecule antibody, T cell receptor antibody,T5224, T5226, TA101, TA112, TA383, TA5493, tabalumab, Tacedin, Tacgraf,TACIFc5, Tacrobell, Tacrograf, Tacrol, tacrolimus, Tadekinig alpha,Tadolak, TAFA93, Tafirol Artro, Taizen, TAK603, TAK715, TAK783, Takfa,Taksta, talarozole, Talfin, Talmain, talmapimod, Talmea, Talnif,talniflumate, Talos, Talpain, Talumat, Tamalgen, Tamceton, Tamezon,Tandrilax, tannins, Tannosynt, Tantum, tanzisertib, Tapain-beta,Tapoein, Tarenac, tarenflurbil, Tarimus, Tarproxen, Tauxib, Tazomust,TBR652, TC5619, T-cell, immune regulator 1, ATPase, H+ transporting,lysosomal VO subunit A3 antibody, TCK1, T-cort, T-Dexa, Tecelac, Tecon,teduglutide, Teecort, Tegeline, Tementil, temoporfin, Tencam, Tendrone,Tenefuse, Tenfly, tenidap sodium, Tenocam, Tenoflex, Tenoksan, Tenotil,tenoxicam, Tenoxim, Tepadina, Teracort, Teradol, tetomilast, TG0054,TG1060, TG20, TG20, tgAAC94, Th1/Th2 Cytokine Synthase Inhibitor, Th-17cell inhibitors, Thalido, thalidomide, Thalomid, Themisera, Thenil,Therafectin, Therapyace, thiarabine, Thiazolopyrimidines, thioctic acid,thiotepa, THR090717, THR0921, Threenofen, Thrombate III, Thymic peptide,Thymodepressin, Thymogam, Thymoglobulin, Thymoglobuline, Thymojectthymic peptides, thymomodulin, thymopentin, thymopolypetides,tiaprofenic acid, tibezonium iodide, Ticoflex, tilmacoxib, Tilur,T-immune, Timocon, Tiorase, Tissop, TKB662, TL011, TLR4 antagonists,TLR8 inhibitor, TM120, TM400, TMX302, TNF Alpha inhibitor, TNF alpha-TNFreceptor antagonist, TNF antibody, TNF receptor superfamily antagonists,TNF TWEAK Bi-Specific, TNF-Kinoid, TNFQb, TNFR1 antagonist, TNR001,TNX100, TNX224, TNX336, TNX558, tocilizumab, tofacitinib, Tokuhon happ,TOL101, TOL102, Tolectin, ToleriMab, Tolerostem, Tolindol, toll-likereceptor 4 antibody, toll-like receptor antibody, tolmetin sodium,Tongkeeper, Tonmex, Topflame, Topicort, Topleucon, Topnac, ToppinIchthammol, toralizumab, Toraren, Torcoxia, Toroxx, Tory, Toselac,Totaryl, Touch-med, Touchron, Tovok, Toxic apis, Toyolyzom, TP4179,TPCA1, TPI526, TR14035, Tradil Fort, Traficet-EN, Tramace, tramadolhydrochloride, tranilast, Transimune, Transporina, Tratul, Trexall,Triacort, Triakort, Trialon, Triam, triamcinolone, triamcinoloneacetate, triamcinolone acetonide, triamcinolone acetonide acetate,triamcinolone hexacetonide, Triamcort, Triamsicort, Trianex, Tricin,Tricort, Tricortone, TricOs T, Triderm, Trilac, Trilisate, Trinocort,Trinolone, Triolex, triptolide, Trisfen, Trivaris, TRK170, TRK530,Trocade, trolamine salicylate, Trolovol, Trosera, Trosera D, Troycort,TRX1 antibody, TRX4, Trymoto, Trymoto-A, TT301, TT302, TT32, TT32, TT33,TTI314, tumor necrosis factor, tumor necrosis factor 2-methoxyethylphosphorothioate oligonucleotide, tumor necrosis factor antibody, tumornecrosis factor kinoid, tumor necrosis factor oligonucleotide, tumornecrosis factor receptor superfamily, member 1B antibody, tumor necrosisfactor receptor superfamilylB oligonucleotide, tumor necrosis factorsuperfamily, member 12 antibody, tumor necrosis factor superfamily,member 4 antibody, tumor protein p53 oligonucleotide, tumour necrosisfactor alpha antibody, TuNEX, TXA127, TX-RAD, TYK2 inhibitors, Tysabri,ubidecarenone, Ucerase, ulodesine, Ultiflam, Ultrafastin, Ultrafen,Ultralan, U-Nice-B, Uniplus, Unitrexate, Unizen, Uphaxicam, UR13870,UR5269, UR67767, Uremol-HC, Urigon, U-Ritis, ustekinumab, V85546,Valcib, Valcox, valdecoxib, Valdez, Valdixx, Valdy, Valentac, Valoxib,Valtune, Valus AT, Valz, Valzer, Vamid, Vantal, Vantelin, VAP-1 SSAOInhibitor, vapaliximab, varespladib methyl, Varicosin, Varidase,vascular adhesion protein-1 antibody, VB110, VB120, VB201, VBY285,Vectra-P, vedolizumab, Vefren, VEGFR-1 Antibody, Veldona, veltuzumab,Vendexine, Venimmun N, Venoforte, Venoglobulin-IH, Venozel, Veral,Verax, vercirnon, vero-Dexamethasone, Vero-Kladribin, Vetazone, VGX1027,VGX750, Vibex MTX, vidofludimus, Vifenac, Vimovo, Vimultisa, Vincort,Vingraf, Vioform-HC, Vioxl, Vioxx, Virobron, visilizumab, Vivaglobin,Viva1de Plus, Vivian-A, VLST002, VLST003, VLST004, VLST005, VLST007,Voalla, voclosporin, Vokam, Vokmor, Volmax, Volna-K, Voltadol,Voltagesic, Voltanase, Voltanec, Voltaren, Voltarile, Voltic, Voren,vorsetuzumab, Votan-SR, VR909, VRA002, VRP1008, VRS826, VRS826, VT111,VT214, VT224, VT310, VT346, VT362, VTX763, Vurdon, VX30 antibody, VX467,VXS, VX509, VX702, VX740, VX745, VX745, VX850, W54011, Walacort, Walix,WC3027, Wilgraf, Winflam, Winmol, Winpred, Winsolve, Wintogeno, WIP901,Woncox, WSB711 antibody, WSB712 antibody, WSB735, WSB961, X071NAB,X083NAB, Xantomicin Forte, Xedenol, Xefo, Xefocam, Xenar, Xepol, X-Flam,Xibra, Xicam, Xicotil, Xifaxan, XL499, XmAb5483, XmAb5485, XmAb5574,XmAb5871, XOMA052, Xpress, XPro1595, XtendTNF, XToll, Xtra, Xylex-H,Xynofen SR, Yang Shu-IVIG, YHB14112, YM974, Youfeline, Youfenac, Yuma,Yumerol, Yuroben, YY piroxicam, Z104657A, Zacy, Zaltokin, zaltoprofen,Zap70 Inhibitor, Zeepain, Zeloxim Fort, Zema-Pak, Zempack, Zempred,Zenapax, Zenas, Zenol, Zenos, Zenoxone, Zerax, Zerocam, Zerospasm, ZFNs,zinc oxide, Zipsor, ziralimumab, Zitis, Zix-S, Zocort, Zodixam,Zoftadex, zoledronic acid, Zolfin, Zolterol, Zopyrin, Zoralone, ZORprin,Zortress, ZP1848, zucapsaicin, Zunovate, Zwitterionic polysaccharides,ZY1400, Zybodies, Zycel, Zyrofen, Zyrogen Inhibitors, Zyser, Zytrim, andZywin-Forte. In addition, the anti-inflammatory drugs, as listed above,may be combined with one or more agents listed above or herein or withother agents known in the art.

In one embodiment, a drug that reduces, inhibits, prevents and/orameliorates inflammation, for example, one of the drugs provided above,is delivered to the suprachoroidal space of the eye using themicroneedle devices and methods disclosed herein, and is used to treat,prevent and/or ameliorate a disease or disorder selected from arthritis,degenerative arthritis, psoriatic arthritis, arthritic disorders,arthritic pain, arthrosis, autoimmune arthritis, autoimmune diseases,autoimmune disorders, axial spondyloarthritis, chronic prosthetic jointinfection, collagen induced arthritis, osteoarthritis, rheumatoidarthritis, senile arthritis, seronegative oligoarthritis of the knee,allergic and autoimmune inflammatory diseases, inflammatory diseases,inflammatory disorders, collagen diseases, discoid Lupus Erythematosus,immune deficiencies, immune diseases, immune disorders, immunodeficiencydiseases, immunodeficiency disorders, immunoglobulin (IgG2) deficiency,immunoglobulin deficiency, Inflammation, Lambert-Eaton myastheniasyndrome, polymyositis, dermatomyositis, polyneuritis, post-operativeocular inflammation, polychondritis, sporadic inclusion body myositis,Systemic Lupus Erythematosus, T cell deficiency, TNF-receptor associatedperiodic syndrome, tropical spastic paraparesis, Wegener Granulomatosis,X-linked severe combined immunodeficiency disease, Behcet's disease,Crohn's disease, Crohn's Fistula, cutaneous Lupus Erythematosus, acuteinflammation, acute inflammatory edema, adrenocortical insufficiency,cerebral inflammation, chronic lung inflammation, corticoid-responsiveinflammatory skin disorders, cutaneous inflammation, dermalinflammation, dry skin inflammatory disease, ear edema, earinflammation, glossitis, inflammatory bowel disease, inflammatorydegenerative disease, inflammatory disorders of the eye and/or ear,inflammatory lesions in fungal infections, inflammatory lesions,inflammatory pain, inflammatory skin diseases or disorders, mouth andgum inflammation, mouth and throat inflammation, musculoskeletaldisorders, otitis, pelvic inflammatory disease, perianal inflammation,post operative inflammation, pulmonary inflammation, rectalinflammation, refractory idiopathic inflammatory myopathies, seborrhoeicdermatitis, swelling, aphthous ulcerations, chronic polyarthritis,juvenile rheumatoid arthritis, rheumatic diseases, Sjogren's syndrome,opthalmic for Sjogren's syndrome, transplant rejection, acute allograftrejection, chronic graft rejection, graft versus host disease, humoralrejection in heart transplantation, humoral rejection in kidneytransplantation, organ rejection in renal transplantation, solid organtransplant rejection, bronchiolitis obliterans after lungtransplantation, rejection of bone marrow transplant, chronic lungtransplant rejection, Corneal graft rejection, delayed graft function inkidney transplantation, heart transplant rejection, Homotransplantationrejection, immune rejection of hESC-derived therapeutic grafts, kidneytransplant rejection, liver transplant rejection, lung transplantrejection, organ rejection, pancreatic islet transplantation rejectionin type I diabetes, renal transplant rejection and xenograft rejection.

In one embodiment, the drug delivered to the suprachoroidal space usingthe microneedle devices and methods disclosed herein treats, prevents,and/or ameliorates macular degeneration (e.g., age related maculardegeneration, dry age related macular degeneration, exudativeage-related macular degeneration, geographic atrophy associated with agerelated macular degeneration, neovascular (wet) age-related maculardegeneration, neovascular maculopathy and age related maculardegeneration, occult with no classic choroidal neovascularization (CNV)in age-related macular degeneration, Stargardt's disease, Subfoveal wetAge-Related macular degeneration, and Vitreomacular Adhesion (VMA)associated with Neovascular Age Related macular degeneration). Examplesof drugs that treat, prevent and/or ameliorate macular degeneration thatcan be used in conjunction with the devices and methods described hereininclude, but are not limited to: A0003, A36 peptide, AAV2-sFLT01,ACE041, ACU02, ACU3223, ACU4429, AdPEDF, aflibercept, AG13958,aganirsen, AGN150998, AGN745, AL39324, AL78898A, AL8309B, ALN-VEG01,alprostadil, AM1101, amyloid beta antibody, anecortave acetate,Anti-VEGFR-2 Alterase, Aptocine, APX003, ARC1905, ARC1905 with Lucentis,ATG3, ATP-binding cassette, sub-family A, member 4 gene, ATXS10, Avastinwith Visudyne, AVT101, AVT2, bertilimumab, bevacizumab with verteporfin,bevasiranib sodium, bevasiranib sodium; with ranibizumab, brimonidinetartrate, BVA301, canakinumab, Cand5, Cand5 with Lucentis, CERE140,ciliary neurotrophic factor, CLT009, CNT02476, collagen monoclonalantibody, complement component 5 aptamer (pegylated), complementcomponent 5 aptamer (pegylated) with ranibizumab, complement componentC3, complement factor B antibody, complement factor D antibody, copperoxide with lutein, vitamin C, vitamin E, and zinc oxide, dalantercept,DE109, dexamethasone with ranibizumab and verteporfin, disitertide, DNAdamage inducible transcript 4 oligonucleotide, E10030, E10030 withLucentis, EC400, eculizumab, EGP, EHT204, embryonic stem cells, humanstem cells, endoglin monoclonal antibody, EphB4 RTK Inhibitor, EphB4Soluble Receptor, ESBA1008, ETX6991, Evizon, Eyebar, EyePromise Five,Eyevi, Eylea, F200, FCFD4514S, fenretinide, fluocinolone acetonide,fluocinolone acetonide with ranibizumab, fms-related tyrosine kinase 1oligonucleotide, fms-related tyrosine kinase 1 oligonucleotide withkinase insert domain receptor 169, fosbretabulin tromethamine, Gamunex,GEM220, GS101, GSK933776, HC31496, Human n-CoDeR, HYB676, IBI-20089 withLucentis, iCo-008, Iconl, I-Gold, Ilaris, Iluvien, Iluvien withLucentis, immunoglobulins, integrin alpha5beta1 immunoglobulinfragments, Integrin inhibitor, IRIS Lutein, I-Sense Ocushield, Isonep,isopropyl unoprostone, JPE1375, JSM6427, KH902, LentiVue, LFG316, LP590,LPO1010AM, Lucentis, Lucentis with Visudyne, Lutein ekstra, Lutein withmyrtillus extract, Lutein with zeaxanthin, M200, M200 with Lucentis,Macugen, MC1101, MCT355, mecamylamine, Microplasmin, motexafin lutetium,MP0112, NADPH oxidase inhibitors, Neoretna, neurotrophin 4 gene,Nova21012, Nova21013, NT501, NT503, Nutri-Stulln, ocriplasmin, OcuXan,Oftan Macula, Optrin, ORA102 with Avastin, P144, P17, Palomid 529,PAN90806, Panzem, Panzem, PARP Inhibitors, pazopanib hydrochloride,pegaptanib sodium, PF4523655, PG11047, piribedil, platelet-derivedgrowth factor beta polypeptide aptamer (pegylated), platelet-derivedgrowth factor beta polypeptide aptamer (pegylated) with ranibizumab,PLG101, PMX20005, PMX53, POT4, PRS055, PTK787, ranibizumab, ranibizumabwith triamcinolone acetonide, ranibizumabwith verteporfin, ranibizumabwith volociximab, RD27, Rescula, Retaane, retinal pigment epithelialcells, RetinoStat, RG7417, RN6G, RT101, RTU007, SB267268, serpinpeptidase inhibitor, clade F, member 1 gene, shark cartilage extract,Shefl, SIR1046, SIR1076, Sirna027, sirolimus, SMTD004, Snelvit, SODMimetics, Soliris, sonepcizumab, squalamine lactate, ST602, StarGen,T2TrpRS, TA106, talaporfin sodium, Tauroursodeoxycholic acid, TG100801,TKI, TLCx99, TRC093, TRC105, triamcinolone acetonide with verteporfin,Trivastal Retard, TT30, Ursa, ursodiol, Vangiolux, VAR10200, vascularendothelial growth factor antibody, vascular endothelial growth factorB, vascular endothelial growth factor kinoid, vascular endothelialgrowth factor oligonucleotide, VAST Compounds, vatalanib, VEGFInhibitor, verteporfin, Visudyne, Visudyne with Lucentis anddexamethasone, Visudyne with triamcinolone acetonide, Vivis,volociximab, Votrient, XV615, zeaxanthin, ZFP TF, zinc-monocysteine andZybrestat. In one embodiment, one or more of the macular degenerationtreating drugs described above is combined with one or more agentslisted above or herein or with other agents known in the art.

In one embodiment, the methods and devices provided hererin are used todelivery triamcinolone or triamcinolone acetonide to the suprachoroidalspace of an eye of a patient in need thereof. In a further embodiment,the triamcinolone or triamcinolone acetonide is delivered for thetreatment of sympathetic ophthalmia, temporal arteritis, uveitis and/orocular inflammatory conditions. In one embodiment, triamcinolone ortriamcinolone acetonide is delivered to the suprachoroidal space of theeye in a patient in need of treatment of sympathetic opthalmia with themethods and devices described herein. In another embodiment,triamcinolone or triamcinolone acetonide is delivered to thesuprachoroidal space of the eye in a patient in need of treatment oftemporal arteritis with the methods and devices described herein. In yetanother embodiment, triamcinolone or triamcinolone acetonide isdelivered to the suprachoroidalspace of the eye in a patient in need oftreatment of uveitis, with the methods and devices described herein. Inanother embodiment, triamcinolone or triamcinolone acetonide isdelivered to the suprachoroidal space of the eye in a patient in need oftreatment of one or more ocular inflammatory conditions, with themethods and devices described herein.

The triamcinolone composition provided herein, in one embodiment, is asuspension comprising microparticles or nanoparticles of triamcinoloneor triamcinolone acetonide. The microparticles, in one embodiment, havea D50 of about 3 μm or less. In a further embodiment, the D₅₀ is about 2μm. In another embodiment, the D₅₀ is about 2 μm or less. In evenanother embodiment, the D₅₀ is about 1000 nm or less. Themicroparticles, in one embodiment, have a D₉₉ of about 10 μm or less. Inanother embodiment, the D₉₉ is about 10 μm. In another embodiment, theD₉₉ is less than about 10 μm or less than about 9 μm or less.

In one embodiment, the triamcinolone composition comprises triamcinolonemicroparticles. In a further embodiment, the composition comprisespolysorbate 80. In another embodiment, the triamcinolone compositioncomprises one or more of CaCl₂, MgCl₂, sodium acetate and sodiumcitrate. In one embodiment, the composition comprises polysorbate 80 ata w/v % of 0.02% or about 0.02%, 0.015% or about 0.015%.

In certain embodiments the drug delivered to ocular tissues using themicroneedle devices and methods disclosed herein treats, prevents,and/or ameliorates fibrosis (e.g. myelofibrosis, fibrosis in diabeticnephropathy, cystic fibrosis, scarring, and skin fibrosis).

In one embodiment, a drug that treats, prevents and/or amelioratesfibrosis is used in conjunction with the devices and methods describedherein, and is delivered to the suprachoroidal space of the eye. In afurther embodiment, the drug is Actimmune with Pirfenidone, ACUHTR028,AlphaVBeta5, aminobenzoate potassium, amyloid P, ANG1122, ANG1170,ANG3062, ANG3281, ANG3298, ANG4011, Anti-CTGF RNAi, Aplidin, Astragalusmembranaceus extract with salvia and schisandra chinensis,atherosclerotic plaque blocker, Azol, AZX100, BB3, connective tissuegrowth factor antibody, CT140, danazol, Esbriet, EXC001, EXC002, EXC003,EXC004, EXC005, F647, FG3019, Fibrocorin, Follistatin, FT011, Galectin-3inhibitors, GKT137831, GMCT01, GMCT02, GRMD01, GRMD02, GRN510, HeberonAlfa R, interferon alfa-2b, interferon gamma-1b with pirfenidone,ITMN520, JKB119, JKB121, JKB122, KRX168, LPA1 receptor antagonist,MGN4220, MIA2, microRNA 29a oligonucleotide, MMI0100, noscapine,PBI4050, PBI4419, PDGFR inhibitor, PF-06473871, PGN0052, Pirespa,Pirfenex, pirfenidone, plitidepsin, PRM151, Px102, PYN17, PYN22 withPYN17, Relivergen, rhPTX2 Fusion Proteins, RXI109, secretin, STX100,TGF-beta Inhibitor, transforming growth factor, beta receptor 2oligonucleotide, VA999260 or XV615. In one embodiment, one or more ofthe fibrosis treating drugs described above is combined with one or moreagents listed above or herein or with other agents known in the art.

In one embodiment, a drug that treats, prevents and/or amelioratesdiabetic macular edema is used in conjunction with the devices andmethods described herein, and is delivered to the suprachoroidal spaceof the eye. In a further embodiment, the drug is AKB9778, bevasiranibsodium, Candy, choline fenofibrate, Cortiject, c-raf 2-methoxyethylphosphorothioate oligonucleotide, DE109, dexamethasone, DNA damageinducible transcript 4 oligonucleotide, FOV2304, iCo007, KH902, MP0112,NCX434, Optina, Ozurdex, PF4523655, SAR1118, sirolimus, SK0503 orTriLipix. In one embodiment, one or more of the diabetic macular edematreating drugs described above is combined with one or more agentslisted above or herein or with other agents known in the art.

In one embodiment, a drug that treats, prevents and/or amelioratesmacular edema is used in conjunction with the devices and methodsdescribed herein, and is delivered to the suprachoroidal space of theeye. In a further embodiment, the drug is denufosol tetrasodium,dexamethasone, ecallantide, pegaptanib sodium, ranibizumab ortriamcinolone. In addition, the drugs delivered to ocular tissues usingthe microneedle devices and methods disclosed herein which treat,prevent, and/or ameliorate macular edema, as listed above, may becombined with one or more agents listed above or herein or with otheragents known in the art.

In one embodiment, a drug that treats, prevents and/or amelioratesocular hypertension is used in conjunction with the devices and methodsdescribed herein and is delivered to the suprachoroidal space of theeye. In a further embodiment, the drug is 2-MeS-beta gamma-CCl2-ATP,Aceta Diazol, acetazolamide, Aristomol, Arteoptic, AZD4017, Betalmic,betaxolol hydrochloride, Betimol, Betoptic S, Brimodin, Brimonal,brimonidine, brimonidine tartrate, Brinidin, Calte, carteololhydrochloride, Cosopt, CS088, DE092, DE104, DE111, dorzolamide,dorzolamide hydrochloride, Dorzolamide hydrochloride with Timololmaleate, Droptimol, Fortinol, Glaumol, Hypadil, Ismotic, isopropylunoprostone, isosorbide, Latalux, latanoprost, Latanoprost with Timololmaleate, levobunolol hydrochloride, Lotensin, Mannigen, mannitol,metipranolol, mifepristone, Mikelan, Minims Metipranolol, Mirol,nipradilol, Nor Tenz, Ocupress, olmesartan, Ophtalol, pilocarpinenitrate, Piobaj, Rescula, RU486, Rysmon TG, SAD448, Saflutan, Shemol,Taflotan, tafluprost, tafluprost with timolol, Thiaboot, Timocomod,timolol, Timolol Actavis, timolol hemihydrate, timolol maleate, Travast,travoprost, Unilat, Xalacom, Xalatan or Zomilol. In addition, the drugsdelivered to ocular tissues using the microneedle devices and methodsdisclosed herein which treat, prevent, and/or ameliorate ocularhypertension, as listed above, may be combined with one or more agentslisted above or herein or with other agents known in the art.

In certain embodiments one or more drugs may be delivered to oculartissues and/or into the suprachoroidal space via the systems and devicesdescribed herein. Delivery of one or more drugs into the suprachoroidalspace using the microneedle device described herein may be accomplishedby using one or more microneedles. In addition, combinations of one ofmore drugs may be delivered to the suprachoroidal space using themicroneedle device described herein in combination with delivery of oneor more drugs via intravitreal (IVT) administration (e.g., intravitrealinjection, intravitreal implant or eye drops). Methods of IVTadministration are well known in the art. Examples of drugs that can beadministered via IVT include, but are not limited to: A0003, A0006,Acedolone, AdPEDF, aflibercept, AG13958, aganirsen, AGN208397, AKB9778,AL78898A, amyloid P, Angiogenesis Inhibitor Gene Therapy, ARC1905,Aurocort, bevasiranib sodium, brimonidine, Brimonidine, brimonidinetartrate, bromfenac sodium, Candy, CERE140, Ciganclor, CLT001, CLT003,CLT004, CLT005, complement component 5 aptamer (pegylated), complementfactor D antibody, Cortiject, c-raf 2-methoxyethyl phosphorothioateoligonucleotide, cyclosporine, triamcinolone, DE109, denufosoltetrasodium, dexamethasone, dexamethasone phosphate, disitertide, DNAdamage inducible transcript 4 oligonucleotide, E10030, ecallantide,EG3306, Eos013, ESBA1008, ESBA105, Eylea, FCFD4514S, fluocinoloneacetonide, fms-related tyrosine kinase 1 oligonucleotide, fomivirsensodium, fosbretabulin tromethamine, FOV2301, FOV2501, ganciclovir,ganciclovir sodium, GS101, GS156, hyaluronidase, IBI20089, iCo007,Iluvien, INS37217, Isonep, JSM6427, Kalbitor, KH902, lerdelimumab,LFG316, Lucentis, M200, Macugen, Makyueido, Microplasmin, MK0140,MP0112, NCX434, neurotrophin 4 gene, OC10X, ocriplasmin, ORA102,Ozurdex, P144, P17, Palomid 529, pazopanib hydrochloride, pegaptanibsodium, Plasma Kallikrein Inhibitors, platelet-derived growth factorbeta polypeptide aptamer (pegylated), POT4, PRM167, PRS055, QPI1007,ranibizumab, resveratrol, Retilone, retinal pigment epithelium-specificprotein 65 kDa gene, Retisert, rod derived cone viability factor, RPE65Gene Therapy, RPGR Gene Therapy, RTP801, Sd-rxRNA, serpin peptidaseinhibitor clade F member 1 gene, Sirna027, sirolimus, sonepcizumab,SRT501, STP601, TG100948, Trabio, triamcinolone, triamcinoloneacetonide, Trivaris, tumor necrosis factor antibody, VEGF/rGel-Op,verteporfin, Visudyne, Vitrase, Vitrasert, Vitravene, Vitreals,volociximab, Votrient, XG102, Xibrom, XV615, and Zybrestat. Accordingly,the methods of the present invention include administrating via IVT oneor more of the drugs listed above in combination with one or more drugsdisclosed herein administered into the suprachoroidal space using themicroneedle device described herein.

In one embodiment, the drug is formulated for storage and delivery viathe microneedle device described herein. The “drug formulation” is aformulation of a drug, which typically includes one or morepharmaceutically acceptable excipient materials known in the art. Theterm “excipient” refers to any non-active ingredient of the formulationintended to facilitate handling, stability, dispersibility, wettability,release kinetics, and/or injection of the drug. In one embodiment, theexcipient may include or consist of water or saline.

In one embodiment, the fluid drug formulation includes microparticles ornanoparticles, each of which can include at least one drug. Desirably,the microparticles or nanoparticles provide for the controlled releaseof drug into the ocular tissue. As used herein, the term “microparticle”encompasses microspheres, microcapsules, microparticles, and beads,having a number average diameter of 1 to 100 μm, most preferably 1 to 25μm. The term “nanoparticles” are particles having a number averagediameter of 1 to 1000 nm. Microparticles may or may not be spherical inshape. “Microcapsules” are defined as microparticles having an outershell surrounding a core of another material. The core can be liquid,gel, solid, gas, or a combination thereof. In one case, the microcapsulemay be a “microbubble” having an outer shell surrounding a core of gas,wherein the drug is disposed on the surface of the outer shell, in theouter shell itself, or in the core. Microbubbles may respond to acousticvibrations as known in the art for diagnosis and/or can be used to burstthe microbubble to release its payload at/into a select ocular tissuesite. “Microspheres” can be solid spheres, can be porous and include asponge-like or honeycomb structure formed by pores or voids in a matrixmaterial or shell, or can include multiple discrete voids in a matrixmaterial or shell. The microparticle or nanoparticles may furtherinclude a matrix material. The shell or matrix material may be apolymer, amino acid, saccharride, or other material known in the art ofmicroencapsulation.

The drug-containing microparticles or nanoparticles may be suspended inan aqueous or non-aqueous liquid vehicle. The liquid vehicle may be apharmaceutically acceptable aqueous solution, and optionally may furtherinclude a surfactant. The microparticles or nanoparticles of drugthemselves may include an excipient material, such as a polymer, apolysaccharide, a surfactant, etc., which are known in the art tocontrol the kinetics of drug release from particles.

In one embodiment, the fluid drug formulation further includes an agenteffective to degrade collagen or GAG fibers in the sclera, which mayenhance penetration/release of the drug into the ocular tissues. Thisagent may be, for example, an enzyme, such a hyaluronidase, acollagenase, or a combination thereof. In a variation of this method,the enzyme is administered to the ocular tissue in a separate stepfrom—preceding or following—infusion of the drug. The enzyme and drugare administered at the same site.

In another embodiment, the drug formulation is one that undergoes aphase change upon administration. For instance, a liquid drugformulation may be injected through hollow microneedles into thesuprachoroidal space, where it then gels and the drug diffuses out fromthe gel for controlled release.

While the embodiments and methods herein describe delivering amedicament to a target tissue, the embodiments described herein can beconfigured to facilitate a biopsy procedure and/or removal of asubstance from a target location.

While the embodiments have been described above in use on ocular tissue,in some instances, the embodiments and methods described herein can beused on any other suitable bodily tissue. For example, in someinstances, the use of an adjustable length needle can be beneficial inconjunction with standard phlebotomy techniques during drug infusionand/or blood draw from a vein. Thus, while the embodiments and methodsare specifically described above in use on ocular tissue, it should beunderstood that the embodiments and methods have been presented by wayof example only, and not limitation.

While various embodiments have been described above, it should beunderstood that they have been presented by way of example only, and notlimitation. Where methods described above indicate certain eventsoccurring in certain order, the ordering of certain events may bemodified. Additionally, certain of the events may be performedconcurrently in a parallel process when possible, as well as performedsequentially as described above.

Although the systems and methods are shown and described herein asproviding for delivery of medicaments in the suprachoroidal space, inother embodiments, the systems and the methods described herein can beapplicable for delivery of any suitable therapeutic substance to anyportion of the eye, such as, the cornea, the retinal area or thevitreous. In other embodiments, any of the systems, methods and devicesdescribed herein can be used to deliver any suitable therapeuticsubstance to any desired target tissue (including non-ocular tissue).

Where schematics and/or embodiments described above indicate certaincomponents arranged in certain orientations or positions, thearrangement of components may be modified. Similarly, where methodsand/or events described above indicate certain events and/or proceduresoccurring in certain order, the ordering of certain events and/orprocedures may be modified. While the embodiments have been particularlyshown and described, it will be understood that various changes in formand details may be made.

For example, although the injector assembly 2100 is shown and describedas including a biasing member 2146 configured to exert a force to movethe actuator 2320 to assist in the delivery of a medicament, in otherembodiments, the injector assembly 2100 (and any other injectorassemblies shown and described herein) can include any suitablemechanism for producing a force to move the actuator 2320. For example,in some embodiments, an injector assembly can include a stored energymember, such as a propellant canister, a compressed gas container, amagnetic energy storage member, an electronic energy storage member(e.g., a battery or a capacitor) or the like.

Although various embodiments have been described as having particularfeatures and/or combinations of components, other embodiments arepossible having a combination of any features and/or components from anyof embodiments as discussed above. For example, while the extractionmember 21280 is described as being included in the system 21000 andconfigured to be coupled to the medicament container 21310, in someembodiments, the device 2000, 3000, or any other device described hereincan be used with and/or include the extraction member 21280, or anyother extraction member described herein. Furthermore, while the needleassembly 3200 is shown as being included in the system 3000, in someembodiments, the system 2000, 21000, or any other medical injectordescribed herein can also include the needle assembly 3200 or any otherneedle assembly described herein. Moreover, while the injection assembly2100 is described as included with the system 2000, in some embodiments,the injection assembly 2100 can also be included in the system 3000,21000 or any other system described herein. Similarly, any of thesystems described herein (e.g., the system 2000, 3000, or 21000) caninclude or configured to be coupled to a hub that includes a convexdistal end surface such as, for example, the hub 7270, 8270, or 9270.

1. An apparatus, comprising: a medicament container, the medicamentcontainer including an adeno-associated virus (AAV); a housingconfigured to receive a portion of the medicament container; a hubconfigured to be coupled to the medicament container and defining apassageway through which a puncture member is disposed, the hub beingfixedly coupled to the puncture member such that the hub moves with thepuncture member when the puncture member is moved relative to an eye, adistal end surface of the hub being configured to contact a targetsurface of the eye when the AAV is conveyed through the puncture member;and an actuation rod at least partially disposed within the medicamentcontainer, the medicament container, the actuation rod, and the puncturemember collectively configured such that (1) a portion of the actuationrod moves within the medicament container in response to amanually-applied force on the actuation rod when a distal end portion ofthe puncture member is disposed within a suprachoroidal space of theeye, and (2) movement of a distal end portion of the actuation rodwithin the medicament container in response to the force on theactuation rod is limited when the distal end portion of the puncturemember is disposed within a portion of a sclera of the eye, the forcehaving a magnitude less than a threshold value.
 2. The apparatus ofclaim 1, wherein the threshold value is from about 2N to about 6N. 3.The apparatus of claim 1, wherein the target surface is any one of aconjunctiva of the eye or the sclera of the eye.
 4. The apparatus ofclaim 1, wherein the distal end surface of the hub includes a sealingportion configured to define a substantially fluid-tight seal with thetarget surface when the AAV is conveyed through the puncture member. 5.The apparatus of claim 4, wherein the sealing portion is symmetricalabout a centerline of the passageway of the hub.
 6. The apparatus ofclaim 1, wherein a centerline of the puncture member is substantiallynormal to a surface line tangent to the hub.
 7. The apparatus of claim1, wherein the force is between about 0.5N and about 2N.
 8. Theapparatus of claim 1, wherein the hub is configured to be coupled to themedicament container via a threaded coupling.
 9. The apparatus of claim1, wherein at least a portion of the medicament container istransparent.
 10. The apparatus of claim 1, wherein the distal endsurface of the hub is convex.
 11. The apparatus of claim 1, wherein acenterline of the puncture member is substantially normal to a surfaceline tangent to the hub, wherein a proximal-most end of the puncturemember terminates within the passageway of the hub, and wherein thedistal end surface of the hub is convex.
 12. A kit, comprising: a vialcontaining an adeno-associated virus (AAV); and a medical injector, themedical injector including: a housing, the housing configured to becoupled to a medicament container; the medicament container, themedicament container configured to receive the AAV from the vial; a hub,the hub configured to be coupled to the medicament container anddefining a passageway through which a puncture member is disposed, thepuncture member being fixedly coupled to the hub, at least a portion ofa distal end surface of the hub having (1) a hemispherical shape, and(2) a sealing portion configured to define a substantially fluid-tightseal with a target surface of an eye when the AAV is conveyed throughthe puncture member; and an actuation rod, the actuation rod configuredto be at least partially disposed within the medicament container, themedicament container, the actuation rod, and the puncture membercollectively configured such that (1) a portion of the actuation rodmoves within the medicament container in response to a manually-appliedforce on the actuation rod when a distal end portion of the puncturemember is disposed within a suprachoroidal space of the eye, and (2)movement of a distal end portion of the actuation rod within themedicament container in response to the force on the actuation rod islimited when the distal end portion of the puncture member is disposedwithin a portion of a sclera of the eye, the force having a magnitudeless than a threshold value.
 13. The kit of claim 12, wherein thethreshold value is from about 2N to about 6N.
 14. The kit of claim 12,wherein the target surface is any one of a conjunctiva of the eye or thesclera of the eye.
 15. The kit of claim 12, wherein the sealing portionis symmetrical about a centerline of the passageway of the hub.
 16. Thekit of claim 12, wherein a centerline of the puncture member issubstantially normal to a surface line tangent to the hub.
 17. The kitof claim 12, wherein the force is between about 0.5N and about 2N. 18.The kit of claim 12, wherein the hemispherical shape is convex.
 19. Thekit of claim 12, wherein the hub is configured to be coupled to themedicament container via a threaded coupling.
 20. The kit of claim 12,wherein at least a portion of the medicament container is transparent.21. The kit of claim 12, wherein the hub is a first hub and the puncturemember is a first puncture member, the kit further comprising a secondhub and a second puncture member fixedly coupled to the second hub, thesecond hub configured to be coupled to the medicament container when thefirst hub is not coupled to the medicament container.
 22. An apparatus,comprising: a medicament container configured to contain anadeno-associated virus (AAV); a housing configured to receive a portionof the medicament container; a hub configured to be coupled to themedicament container and defining a passageway through which a puncturemember is disposed, the hub being fixedly coupled to the puncture membersuch that the hub moves with the puncture member when the puncturemember is moved relative to an eye, at least a portion of a distal endsurface of the hub having a convex shape, the hub being configured tocontact a target surface of the eye when the AAV is conveyed through thepuncture member, a proximal-most end of the puncture member terminatingwithin the passageway of the hub; and an actuation rod at leastpartially disposed within the medicament container, the medicamentcontainer, the actuation rod, and the puncture member collectivelyconfigured such that (1) a portion of the actuation rod moves within themedicament container in response to a force on the actuation rod when adistal end portion of the puncture member is disposed within asuprachoroidal space of the eye, and (2) movement of a distal endportion of the actuation rod within the medicament container in responseto the force on the actuation rod is limited when the distal end portionof the puncture member is disposed within a portion of a sclera of theeye, the force having a magnitude less than a threshold value.
 23. Theapparatus of claim 22, wherein the threshold value is from about 2N toabout 6N.
 24. The apparatus of claim 22, wherein a centerline of thepuncture member is substantially normal to a surface line tangent to thehub.
 25. The apparatus of claim 22, wherein the force is between about0.5N and about 2N.
 26. The apparatus of claim 22, wherein the force isapplied manually.
 27. The apparatus of claim 22, wherein the portion ofthe sclera is an upper portion of the sclera.